Exercise & COVID

Could exercise help prevent COVID as well as help with post-COVID symptoms?

We’ve spent quite a bit of time detailing some of the benefits of exercise including a review about the field of exercise immunology.

We’ll take some of that information and apply to the current predicament with COVID. Be aware that some of this information may overlap with information presented in prior posts. Also, not many trials have been conducted intrinsically linking exercise and COVID, and so much of the information will be derived from literature reviews and summaries.

Exercise as a Tool against COVID

To summarize, exercise is known to provide anti-inflammatory benefits, helps with mental health and possibly attenuating neurodegenerative damage, as well as helping in altering immunological responses (as outlined in the exercise immunology post).

Exercise Preventing COVID?

Rather than focusing on treatment at the point of infection, it may be more important to examine ways of preventing infection in the first place. Rather than be concerned about dense places or masking, exercise is an activity that everyone should be engaging in that provides benefits that extend beyond just preventing disease.

Nonetheless, exercise may strengthen the immune system to fight against pathogens through preventative means.

A good review is provided by Fernández-Lázaro, et. al.¹ that details some of these immunological changes.

For example, exercise (labeled Ex in the review) may modulate the expression of different interferons (IFN) within the body which may alter immunological responses.

Interferons are cytokines that are released by different cells in the body and each have different functions. For example, IFN-2 are immune interferons released from natural killer (NK) cells, T-cells, and macrophages.

Interferons have been investigated for several years for their antiviral properties, and many have been used extensively for the treatment of various viral infections (Pestka, S.²):

IFN-αs and IFN-β exhibit a wide breadth of biological activities: antiviral and antiproliferative stimulation of cytotoxic activity (64) of a variety of cells of the immune system (T-cells, natural killer cells, monocytes, macrophages, dendritic cells); increasing the expression of tumor-associated surface antigens and other surface molecules such as major histocompatibility complex (MHC) class I antigens (65); induction and/or activation of proapoptotic genes and proteins (e.g. TRAIL, caspases, Bak, and Bax); repression of antiapoptotic genes (e.g. Bcl-2, IAP (inhibitor of apoptosis protein)); modulation of differentiation; and antiangiogenic activity. All of these actions make interferon a most promising agent for the treatment of various diseases (supplemental Fig. 5).

Of note, IFN-2 (γ)³ levels may increase due to exercise, which has several antiviral properties (Fernández-Lázaro, et. al, emphasis mine):

Regular Ex modulates another novel INF pathway, with a probable COVID-19 prevention activity. Ex is beneficial for maintaining the improvement of the immune status, associated with a rise in IFN-2 (γ) in the plasma [25]. Thus, regular moderate Ex seems to modulate its release and increase its levels to those necessary for the human body to maintain good health [26]. Recently, Kang et al. [27] have described the antiviral properties of IFN-γ with its ability to block the virus’s entry into the extracellular and intracellular phases of replication. The pathways of action of IFN-γ are diverse: alteration of the niche of replication, stopping of the process of gene expression, unstructuring the virus by breaking the assembly of the nucleocapsid, and prevention of viral reactivation by inhibiting the transcription of a master regulator of the virus. This mechanism is to accentuate the direct antiviral pathways of IFN-γ that may be stimulated by Ex practice [26]. Effective innate immune response is associated with IFN-α, IFN-β, and IFN-γ, and may play a role in a protective or destructive response against COVID-19 [28]. Therefore, physical exercise could be a tool, through the immune system, that modulates the reactions of the INF pathway that could control viral replication and induce a more adequate immune response.

What’s interesting is that IFN therapy has been looked at extensively with respect to COVID. Some results seemed promising, although the CDC has prevented its use for COVID:

Although many of these issues may be a result of late-stage use of IFN.

IFNs have many antiviral properties, but as cytokines also play a role in stimulating inflammation. In severe COVID there is a likelihood that IFN may exacerbate the systemic inflammation that occurs in severe forms of the disease.

However, the evidence does suggest that early use of IFN treatment may be beneficial. Therefore, this may be another example of early treatment being best.

Interestingly enough, much research has been done in examining a specific gene called the OAS1 gene and its relationship to COVID severity. OAS1 stands for 2'-5'-oligoadenylate synthetase 1, and it is involved with the synthesis of many antiviral proteins involved with the innate immune system. Research has suggested that carriers of the OAS1 isoform found in Neanderthals may be more protected against COVID⁴, and that higher levels of OAS1 is related to better COVID outcomes.

More recently, research into a different OAS1 haplotype has found that carriers of such haplotypes (as seen in some European and African populations) had reduced levels of OAS1 expression, leading to worse COVID outcomes⁵.

OAS1 is induced by IFNs, meaning that higher levels of IFNs may lead to greater expression of OAS1 and thus attenuated outcomes with COVID. In the recent OAS1 study from Banday, et. al. researchers provided either IFN-β or IFN-λ to in vitro Caco2 cell lines carrying the risk haplotypes for reduced OAS1 expression, and found that IFN treatment may compensate for loss of OAS1 expression:

To explore whether interferon treatment could prevent or reduce infection in vitro, we treated infection-permissive intestinal cells Caco224,25 (heterozygous for OAS1 rs10774671 and rs1131454) with IFN-β or IFN-λ 4 h before or after SARS-CoV-2 infection.

All treatments significantly decreased viral loads (Fig. 7a,b and Supplementary Table 6). In the same cells, OAS1 expression was minimally induced by SARS-CoV-2 alone but was strongly induced by before and after treatment with both interferons (Fig. 7c and Supplementary Table 7). Interferon-induced expression of both OAS1-p42 and p46 isoforms was also detectable by western blotting (Supplementary Fig. 3). These results suggested that interferons can generate robust immune response even in SARS-CoV-2-infected cells, inducing expression of both OAS1-p42 and OAS1-p46 isoforms and compensating for any loss of their expression due to NMD.

Piecing all of this together, the evidence suggests that exercise may increase IFN levels, increase expression of OAS1, and thus lead to better COVID outcomes.

Considering that many studies are underway looking at exogenous administration of IFNs, why not exercise and produce many of the IFNs ourselves? This is another example of how we can help ourselves by doing this that we should already be doing via exercise.

There’s also a possibility that innate immune cells may be influenced by exercise (Fernández-Lázaro, et. al.):

The neutrophils, innate immune cells, respond to exercise-derived stimuli. The chemotaxis and phagocytosis increase after moderate activity Ex (50% maximal oxygen uptake (VO2max)) but not in strenuous Ex (80% VO2max), where neutrophils oxidative activity is attenuated [30]. Monocyte cells are mobilized with moderate duration (<60 min) and intensity (<60% VO2max) Ex [10]. Both non-lymphocyte cells (monocytes and phagocytes) present phenotypes related to: (i) effector or cytotoxic functions and differentiated or mature (CD16+ monocytes and CD16− neutrophils); and (ii) integrin and intracellular adhesion molecules, and a range of chemokine receptors, such as CCR5, CCR6, CXCR1, CXCR2, CXCR3, and CXCR4, that have ligands for activated endothelium and permit tissue migration [31]. Lower et al. [9] exercised mice using a motorized treadmill at a speed of 8–12 min at a 1 and 5% grade for 30 min. The treadmill speed was approximately 55–65% of VO2max [9]. In this study [9], this increased the expression of IL-4 and the eotaxins. The eotaxins act as a chemoattractant for eosinophils with granules [32]. The granules contain abundant ribonucleases that degrade single-stranded RNA viruses [32], such as SARS-CoV-2. Moreover, Qin et al. [33] have demonstrated a pronounced lymphopenia (decrease CD3+) in COVID-19. However, Ex stimulates natural killer T (NKT) cells, which have a regulatory effect depending on IL-4 and considerably increase two-fold by Ex [9]. NKT cells are a broad group of CD3+ T cells co-expressing the T cell antigen receptor (TCR) and NK cell markers [34]. The cell trafficking in response to Ex could be a strategy of boosting the innate immune response [26,30] required to eliminate COVID-19 and to prevent the advance of the virus.

As mentioned in the exercise immunology post, deployment of innate immune cells such as monocytes may be a recovery mechanisms after exercise, and so the effects here may be two-fold. They may help aid in recovery while also conducting immunosurveillance, and such activity may increase surveillance and elimination of SARS-COV2 early on during an infection.

So here are just a few additional reasons as to why exercise may aid in innate immune function.

As for the adaptive immune response, we’ve covered much of the benefits previously. In essence, exercise may attenuate senescence of T cells and also lead to apoptosis of older cells in order to make room for newer cells. This assumption is controversial, but if true could provide for better adaptive immune responses by making way for younger, fresher T-cells:

The senescence in T cells (inverted CD4+/CD8+ T cell ratio; increased frequency and proportion of senescent T cells) increases infection susceptibility to novel pathogens [10], such as COVID-19. Regular Ex may facilitate the selective apoptosis of these senescent T cells and stimulate T cells’ replacement [26,30].

The new T cells are capable of responding to novel antigens because they expand the naıve T cell repertoire, alleviate symptoms, and produce biomarkers associated with immunosenescence and the immune risk profile (IRP) [46]. In 102 healthy non-smoker males with 43.0 ± 0.6 VO2max average, this was associated with a lower proportion of senescence and a higher proportion of naïve cells in CD8+ T cells [47]. These may signify that acceptable levels of aerobic status could alone utilize preserving effects on the aging immune system. A healthy lifestyle with practiced regular physical exercise may decrease the risk of host infection. Therefore, Ex could represent the safest and least expensive immunotherapy treatment [48].

B cells respond greatly to exercise, and evidence has suggested that exercise may actually increase the response to vaccination⁶. Paradoxically, an unhealthy lifestyle lacking active movement may actually lead to improper responses to vaccines and may play a role in vaccine effectiveness (note this review came out before the COVID vaccines):

Ex practice has modulated positive plasticity of the immune system [26,30]. A study [58] with 10-month aerobic exercise training showed antibody titers to the H1N1 and H3N2 strains of influenza A virus enhanced in older adults immunized with a trivalent influenza vaccine. Similarly, in different population groups, moderate-intensity Ex improved the response against vaccine strains (influenza, tetanus toxoid, diphtheria, pneumococcal, and meningococcal). However, it caused a significantly more inadequate immune response in the non-exercising group [59]. Finally, in a randomized trial in risk groups susceptible to respiratory virus infections, a 24-week program of moderate cardio-vascular aerobic training was found to significantly increase the seroprotection of subjects from those who only stretched their muscles after receiving the influenza vaccine [60].

In the future, when the COIVID-19 vaccine will be developed, individuals who exercise continuously and regularly may develop higher antibody titers to the SARS-CoV-2 strain contained in the vaccine compared to individuals who do not exercise.

There’s evidence of this from the flu vaccine and obese individuals, which suggests that obese individuals don’t respond well to vaccines⁷, although this response may in part be due to intramuscular vaccines not reaching the proper injection site due to excess adipose. Since obesity is somewhat associated with lack of exercise, we may extrapolate that lack of exercise, especially among obese individuals, may be a problem in vaccinations, although such an assumption may not be warranted considering that several studies already indicate the benefits of exercise post-vaccination.

In short (and a bit redundant), exercise can help both the innate and adaptive immune system respond to viruses, and may provide robust protection before an infection can occur.

Exercise During COVID

Unlike exercise as a prophylactic measure against COVID, exercise while infected is a lot more controversial in nature. For avid exercisers, they may find solace and some necessity in exercising while sick. Some others may see this as a necessary time to wind down and not overdo it if possible. This is also the point in which the “open window” argument may gain prominence, arguing that exercise right at the early stages of an infection may make it worse.

Because of this, not many studies have looked at exercise as a therapeutic against COVID.

One study from Turkey⁸ enrolled COVID-19 participants to see if exercise while infected may lessen the severity of COVID. Both groups were provided medications including Hydroxychlolorquine, but one group was also asked to engage in moderate/intensive exercise for at least 40 minutes per session 3 times a week for two weeks. Essentially, a total of 6 exercise sessions over the course of two weeks (4 hours in total).

In short, the intervention (exercise) group showed greater improvement scores on the Wisconsin survey⁹ and improved biomarkers relative to those who were only given treatment (Mohamed, A. A., & Alawna, M.):

Within-group comparisons showed that the Wisconsin scale total score significantly decreased in both groups (control and intervention) after two weeks of treatment (P < .05). Leucocytes, Lymphocytes, and Interleukin-10 significantly increased in both groups after two weeks of treatment (P < .05). After two weeks of treatment, Interleukin-6, and Immunoglobulin-A significantly increased in the intervention group (P < .05), while it showed non-significant differences in the control group (P > .05). On the other hand, TNF-α showed non-significant differences in the intervention group (P > .05), while it increased significantly in the control group (P < .05). Within-group comparison results are shown in Table 3 .

Although this may seem promising, there are problems with said study, such that the use of self-surveys may bias those who exercised to assume some placebo effect. Participants were also left to conduct the exercises themselves, and therefore may have exercised for longer/shorter than was recommended. Also, although the researchers suggest that participants were matched demographically, the intervention group was nearly 10 years older than the control group with an average age of 44 in the intervention (exercise) group compared to the average age of 35 in the control group.

During an active infection, it’s hard to consider exercise due to the levels of uncertainty- would an infection remain mild, or could it worsen. And if it worsens, could this be due to excess exercise while ill? There may be some benefit to exercising for those within the early stages of the infection who are relatively well, but may be immediately halted if it continues to worsen.

Overall, it’s hard to argue whether exercise during an infection would be appropriate, and instead it may be more important to encourage routine exercise before an infection takes hold and becomes symptomatic in order to improve immune system functions.

Exercise and Post-COVID/Post-Vaccination

From Jimeno-Almazán, et. al. The above schematic diagram shows possible benefits of exercise for those experiencing long COVID.

This is probably one of the most interesting areas, and one that many people may be concerned about. In those with long-COVID, or those who may have experienced adverse events, there may be questions about what is going on and if there is any ways to fix it.

Long COVID is multifaceted, and to this day there still isn’t a full explanation as to what may be occurring.

I’ve written one Anthology Series encapsulating some findings in regards to long COVID, with one section detailing the possible benefits of exercise in managing long COVID:

The Complications of “Long COVID” Part IV

You may not be surprised to find out that exercise’s role in attenuating long COVID is similar to the reasons that it helps prevent severe infection in the first place. Exercise essentially allows for the body to reconfigure its immune response, similar to what we have outlined previously.

For example, this review from Jimeno-Almazán, et. al.¹⁰, which I cited in my long COVID post, makes the same remarks in regards to the beneficial effects of exercise:

Contrary to traditional beliefs, exercise is not detrimental to immune competency but rather can act as an adjuvant to stimulate the immune system by inducing mitochondrial adaptations, cell generation and immune surveillance [73,74,75,76]. Physical fitness status can be a determining modifiable factor for the promotion of metabolic and functional adaptations in T lymphocytes and monocytes, counteracting inflammatory environments caused by expanded adipose tissue and sedentary behaviour, as well as delaying the immunosenescence caused by aging [77]. Regular release of muscle-derived anti-inflammatory cytokines (IL-6, IL-7, IL-10, IL-15), linked with the inhibition of pro-inflammatory cytokines (IL-1β, IL-18, TNF-α), have been purported to play important roles in the beneficial effects of exercise on immunity [75,78,79]. Indeed, there is growing evidence suggesting an anti-carcinogenic effect of exercise through direct changes in circulating proteins, RNA molecules and metabolites [80].

Exercise attenuates immunosenescence by maintaining the peripheral T-cell pool and natural killer cell compartments, and it seems likely to improve the immune response to SARS-CoV-2 antigens [81]. In support of this argument, it has been recently demonstrated that regular, moderate to vigorous physical activity reduced the risk of community-acquired infectious diseases and infectious disease mortality [82]. All in all, it should be noted that exhaustive and excessive exercise training may cause mitochondrial functional impairment, inducing a dysregulated systemic inflammatory response, thus being detrimental for health [83,84,85]. Hence, individually tailored exercise prescriptions among people with post-COVID-19 are essential to elicit positive adaptive changes to enhance immune function.

However, the problem with prescribing exercise is that it’s a lot easier said than done for people experiencing long COVID. One of the most common symptoms of long COVID is fatigue, and so getting people to exercise while they already feel disincentivized to do so may be asking a bit much. In surveys in which people were asked to explain some triggers for long COVID symptoms, exercise was considered to be one of the top triggers¹¹, making it even more difficult to get sufferers of Long COVID to exercise and return to a regimen.

There could be a few explanations for these triggers, such as persistent organ damage leading to the inability to exercise, or an overactive immune system that may exacerbate inflammatory damage during exercise and cause more harm than good.

So far there are no definitive treatments for long COVID, but given the importance of exercise it may be valuable to consider a very slow exercise regimen that increases over time with careful assessment of any long COVID flareups. Sufferers of long COVID may consider discussing exercise with medical professionals and find the right options for them, especially after severe bouts of COVID.

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Exercise to Fight COVID

Much of this information would be considered redundant at this point, but it’s worth highlighting that there are plenty of tools to fight against COVID aside from taking supplements or other forms of therapeutics. It’s not enough to keep taking pills, but doing things that we should already be doing.

Initially, I was going to include an assessment of exercise and whether that would be able to help with the whole “tolerance” situation being brought up. However, that requires further investigation, mostly because the research cited by Brian Mowrey show a Th-2 independent response for class shifting.

I may return back to this series after I find additional information, but I’ll provide you all a break for now!

Just remember that an active lifestyle is one that can prevent illness, and we should therefore find more ways to become active to prevent getting sick from COVID or possibly worse.

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1. Fernández-Lázaro, D., González-Bernal, J. J., Sánchez-Serrano, N., Navascués, L. J., Ascaso-Del-Río, A., & Mielgo-Ayuso, J. (2020). Physical Exercise as a Multimodal Tool for COVID-19: Could It Be Used as a Preventive Strategy?. International journal of environmental research and public health, 17(22), 8496. https://doi.org/10.3390/ijerph17228496

2. Pestka S. (2007). The interferons: 50 years after their discovery, there is much more to learn. The Journal of biological chemistry, 282(28), 20047–20051. https://doi.org/10.1074/jbc.R700004200

3. More information in regards to IFN-γ antiviral activity can be found below (Lin, F. C., & Young, H. A.):

During virus infection, IFN-γ can turn on the cellular antiviral mechanism by inducing the expression of several antiviral proteins. In addition to PKR, OAS and Mx GTPase mentioned in the previous section, IFN-γ can also trigger the expression dsRNA-specific adenosine deaminase (ADAR) which inhibits virus replication by editing or causing mis-translation of viral proteins. Similar to Type I IFNs, IFN-γ can induce apoptosis by up regulating FasL to eliminate virus infected cells. Furthermore, IFN-γ enhances the expression of Type I IFN expression which further augments the antiviral state of the cells. In addition to induction of antiviral proteins, IFN-γ also exercises its antiviral activity by modulating both innate and adaptive immune responses. First, IFN-γ can induce the expression of proinflammatory cytokines and chemokines by endothelial cells, epithelial cells and fibroblasts to recruit macrophages, neutrophils and T cells to the site of infection [40]. Importantly IFN-γ plays a critical role in conveying antiviral signals from the innate to the adaptive immune response in order to fully activate host antiviral immunity. Upon receiving the IFN-γ signal, APCs increase expression of MHC class II and costimulatory molecules which in turn facilitates CD4+ T cell activation and initiation of the adaptive immune response against viral infection. IFN-γ also induces the expression of IL-12 by APCs. IL-12 not only activates NK cells, a major antiviral cellular component of innate immunity, but also drives CD4+ Th1 T cell development, a process that is crucial in controlling viral infection.

• Lin, F. C., & Young, H. A. (2014). Interferons: Success in anti-viral immunotherapy. Cytokine & growth factor reviews, 25(4), 369–376. https://doi.org/10.1016/j.cytogfr.2014.07.015

4. Zhou, S., Butler-Laporte, G., Nakanishi, T. et al. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nat Med 27, 659–667 (2021). https://doi.org/10.1038/s41591-021-01281-1

5. Banday, A.R., Stanifer, M.L., Florez-Vargas, O. et al. Genetic regulation of OAS1 nonsense-mediated decay underlies association with COVID-19 hospitalization in patients of European and African ancestries. Nat Genet 54, 1103–1116 (2022). https://doi.org/10.1038/s41588-022-01113-z

6. Hallam, J., Jones, T., Alley, J., & Kohut, M. L. (2022). Exercise after influenza or COVID-19 vaccination increases serum antibody without an increase in side effects. Brain, behavior, and immunity, 102, 1–10. https://doi.org/10.1016/j.bbi.2022.02.005

7. Sheridan, P. A., Paich, H. A., Handy, J., Karlsson, E. A., Hudgens, M. G., Sammon, A. B., Holland, L. A., Weir, S., Noah, T. L., & Beck, M. A. (2012). Obesity is associated with impaired immune response to influenza vaccination in humans. International journal of obesity (2005), 36(8), 1072–1077. https://doi.org/10.1038/ijo.2011.208

8. Mohamed, A. A., & Alawna, M. (2021). The effect of aerobic exercise on immune biomarkers and symptoms severity and progression in patients with COVID-19: A randomized control trial. Journal of bodywork and movement therapies, 28, 425–432. https://doi.org/10.1016/j.jbmt.2021.07.012

9. The Wisconsin scale is a survey that measures quality of life during an infection. It’s used extensively, although self-reports may heavily bias results. Therefore, care must be used when examining these surveys. It could be that exercise may improve feelings while not actually doing much biochemically. Here, the pairing of the Wisconsin survey along with measured biomarkers may provide validation for the survey results. The researchers provide a rundown of what the Wisconsin survey entails:

The Wisconsin Upper Respiratory Symptom Survey (WURSS) is an empirically derived patient-oriented illness-specific quality-of-life evaluative outcomes instrument (The Wisconsin Upper Respiratory Symptom Survey Is Responsive, Reliable, and Valid) (Barrett et al., 2018). The development process of this survey was described in details by Barrett et al.(The Wisconsin Upper Respiratory Symptom Survey (WURSS): A New Research Instrument for Assessing the Common Cold - PubMed) (Barrett et al., 2018). WURSS-24 is designed to evaluate the negative effect of acute upper respiratory infection, presumed viral (the common cold). It is a validated and reliable measurement method for evaluating the change in the quality of life over time including influenza-like illness symptoms of headache, body aches, and fever (The Wisconsin Upper Respiratory Symptom Survey Is Responsive, Reliable, and Valid; Barrett et al., 2018). The participants were asked to fill the survey before starting the study and after 2 weeks.

10. Jimeno-Almazán, A., Pallarés, J. G., Buendía-Romero, Á., Martínez-Cava, A., Franco-López, F., Sánchez-Alcaraz Martínez, B. J., Bernal-Morel, E., et al. (2021). Post-COVID-19 Syndrome and the Potential Benefits of Exercise. International Journal of Environmental Research and Public Health, 18(10), 5329. MDPI AG. Retrieved from http://dx.doi.org/10.3390/ijerph18105329

11. Davis, H. E., Assaf, G. S., McCorkell, L., Wei, H., Low, R. J., Re'em, Y., Redfield, S., Austin, J. P., & Akrami, A. (2021). Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine, 38, 101019. https://doi.org/10.1016/j.eclinm.2021.101019