PART 8 - EXERCISE AND VIRAL ILLNESS

The following is a review I wrote of the current research on exercise and virial disease. It is a researched review of the academic literature for the Naturopaths and Medical Herbalist of New Zealand Incorporation (NMHNZ). It is just one part of many reviews that the NMHNZ will be forwarding to the government to show that Naturopathic Practice is a research based modality and should be considered an essential service to New Zealand. We can provide an essential service to the public, particularly in the area of prevention and recovery from viral infections (among other things). Due to the nature of this article, many may simply want to read the introduction and the conclusion.

Introduction
It is certainly evident (and should be obvious) that regular exercise is one of the pillars of healthy living. Although often considered to suppress the immune system, epidemiological evidence demonstrates that regular physical activity (both aerobic and resistance training) reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections (Baik et al., 2000; Romaniszyn et al., 2014), as well as non-communicable diseases such as cancer and chronic inflammatory disorders (Warburton & Bredin, 2017).
Naturally, exercise is not the only area of lifestyle that should be addressed when attempting to strengthen the immunity against viral load. However it should be considered of paramount importance when suggesting any health/wellness plan with the benefit of being often free, or of low cost, to an individual. Exercise is also unique in that it can boost our mental health and lower emotional stress, a factor well known in its relation to our immune function.
 
How Does Exercise Strengthen the Immune System
   T Cells
T cells, also called T lymphocytes, are a type of white blood cell that help the body fight infections/diseases and are an essential part of the immune system. In particular, having adequate numbers of naïve T cells is essential for the immune system to continuously respond to new and unfamiliar pathogens. The age-associated decline in immune function, referred to as immunosenescence, is well characterised within the adaptive immune system. Interestingly, a review of the recent evidence shows that regardless of age, an active lifestyle is linked to lower numbers and proportions of memory T cells and higher numbers and proportions of naïve T cells (Campbell & Turner, 2018; Turner, 2016). This study suggests that exercise might exert an anti-immunosenescence effect and prevent the severity of decline of immunity as we age. It is further supported by a recent systematic review, concluding that regular structured exercise increases the number of naïve T cells in peripheral blood at rest (Cao Dinh et al., 2017). However other research indicates that exercise does not need to be regular to have this affect and even a single bout of exercise (albeit transitory) enhances the manufacture of viral-specific T-cells (Simpson et al., 2015; Spielmann et al., 2016).
An overview study of systematic reviews assessed the effectiveness of physical exercise in persons living with Human Immunodeficiency Virus (HIV). Their results suggest that exercise improves outcomes of physiological and psychological health. Although they reported no statistical significance on virological or immunological outcomes, the study did report positive effects of exercise on CD4 counts (the cells that the HIV virus kills) among those studied (Kamitani et al., 2017). This suggests that even though there was no apparent reduction of the virus, there was an improvement in the immune response as a result of exercise. Furthermore, the positive physiological and psychological health outcomes are also part of a healthy immune system. Lastly, Kamitani et al. (2017) suggest that physical exercise appears to be a good strategy to preventing viral spread.
   Natural Killer Cells
With their ability to not only recognise and eliminate virus-infected and neoplastic cells but also to produce immunoregulatory cytokines, natural killer cells (NK-cells) represent an important part of the innate immune system. Exercise mobilises these NK-cells throughout the duration of the exercise and exercise recovery (Zimmer et al., 2017). Muscle-derived exercise factors, known as myokines, regulate NK-cell proliferation, maturation and activation as a response to training (Simpson et al., 2015).
   Antimicrobial Peptides and Proteins
There is a high risk of infection at the epithelial surfaces of the body, such as the skin and respiratory system, that interface with and separate the body from the external environment. These epithelial surfaces are protected from invading microorganisms by the innate mucosal/epithelial defence system. Antimicrobial peptides and proteins (AMPs) are the diverse class of naturally occurring molecules that are produced as a first line of defence in the mucosal immune system. These proteins have a broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. As a constituent product at mucosal surfaces, AMPs participate in the barrier function that prevents microorganisms from causing infection by acting directly on these pathogens. This activity can be lethal to microorganisms, inhibit their growth and activity and/or prevent them from initiating an inflammatory response. AMPs directly kill microbes by a variety of mechanisms, including DNA/RNA disruption, disruption of membranes, degradation of ATP and initiation of autolysins (West et al., 2006).
Exercise has been shown to increase the concentration and secretion rate of each AMP suggesting enhanced immunity and control of inflammation (Gillum et al., 2015). Although the exact mechanism of how the AMP’s are increased has yet to be discovered, the findings of Gillum et al. (2015) are consistent. Although AMPs act directly on microorganisms, they also exert their protective effect via immunomodulatory mechanisms, especially in noninflammatory conditions by recruiting cells, inducing cytokines and aiding in tissue repair (West et al., 2006).
   Upper Respiratory Tract Infections
An Upper Respiratory Tract Infection (URTI) is generally caused by the direct invasion of the inner lining (mucosa or mucus membrane) of the upper airway by a culprit virus or bacteria. As we have seen, the act of exercise promotes the body’s natural defence against virial infections via AMPs, NK-cells and T cells and their immunomodulatory effects. Many of these studies were aimed specifically at URTIs and Acute Respiratory Infection (ARI). One such randomised controlled trial found statistically and clinically significant reductions in ARI illness for participants randomly assigned to 8 weeks of exercise training, compared to observational controls (Barrett et al., 2018). This study interprets the consistent pattern of apparent benefits across their two trials suggesting preventive effects ranging from 14–33% proportional reductions in ARI illness.
 
Does Exercise Suppress the Immune System
It is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. A recent rigorous review article summarising 249 peer-reviewed research papers in the leading journal Frontiers in Immunology, deconstruct the key pillars which lay the foundation to this traditional theory. The review highlights that:

1. Limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections.
2. Purported changes to mucosal immunity (namely salivary IgA levels) after exercise do not signpost a period of immune suppression.
3. The dramatic reductions to lymphocyte numbers and function 1–2 hours after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression.

(Campbell & Turner, 2018)
Furthermore, Campbell and Turner (2018) provide evidence that frequent exercise enhances—rather than suppresses—immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise.
Other research also supports this claim that recent findings challenge early exercise immunology doctrine by showing that international athletes performing high-volume training suffer fewer, not greater, upper respiratory tract infections (Walsh & Oliver, 2016).
 
Conclusion
Although the type, duration and intensity of exercise conducted in the collected research varies, the outcomes were consistent. Whether an endurance athlete or an elderly person taking a 30 minute walk, exercise has a profound effect on the upregulating functioning of the immune system, especially in regards to antiviral defences.
This review highlights that regardless of age, human studies confirm individuals can increase their immunity against viral diseases and limit or delay immunological aging, simply by incorporating mild-moderate exercise into their lifestyle. These effects are immediate after one bout of exercise and do not require a long history of fitness training. The evidence also debunks the myth that exercise temporarily suppresses immune function. We are thereby left with the conclusion that the appropriate form of exercise should provide a protective benefit to all against viral disease.

References
 
Baik, I., Curhan, G. C., Rimm, E. B., Bendich, A., Willett, W. C., & Fawzi, W. W. (2000). A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Archives of Internal Medicine, 160(20), 3082–3088. https://doi.org/10.1001/archinte.160.20.3082
Barrett, B., Hayney, M. S., Muller, D., Rakel, D., Brown, R., Zgierska, A. E., Barlow, S., Hayer, S., Barnet, J. H., Torres, E. R., & Coe, C. L. (2018). Meditation or exercise for preventing acute respiratory infection (MEPARI-2): A randomized controlled trial. PloS One, 13(6), e0197778. https://doi.org/10.1371/journal.pone.0197778
Campbell, J. P., & Turner, J. E. (2018). Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan   . In Frontiers in Immunology   (Vol. 9, p. 648). https://www.frontiersin.org/article/10.3389/fimmu.2018.00648
Cao Dinh, H., Beyer, I., Mets, T., Onyema, O. O., Njemini, R., Renmans, W., De Waele, M., Jochmans, K., Vander Meeren, S., & Bautmans, I. (2017). Effects of Physical Exercise on Markers of Cellular Immunosenescence: A Systematic Review. Calcified Tissue International, 100(2), 193–215. https://doi.org/10.1007/s00223-016-0212-9
Gillum, T. L., Kuennen, M. R., Castillo, M. N., Williams, N. L., & Jordan-Patterson, A. T. (2015). Exercise, but not acute sleep loss, increases salivary antimicrobial protein secretion. Journal of Strength and Conditioning Research, 29(5), 1359–1366. https://doi.org/10.1519/JSC.0000000000000828
Kamitani, E., Sipe, T. A., Higa, D. H., Mullins, M. M., & Soares, J. (2017). Evaluating the Effectiveness of Physical Exercise Interventions in Persons Living  With HIV: Overview of Systematic Reviews. AIDS Education and Prevention : Official Publication of the International Society  for AIDS Education, 29(4), 347–363. https://doi.org/10.1521/aeap.2017.29.4.347
Romaniszyn, D., Pobiega, M., Wojkowska-Mach, J., Chmielarczyk, A., Gryglewska, B., Adamski, P., Heczko, P. B., Ochonska, D., & Bulanda, M. (2014). The general status of patients and limited physical activity as risk factors of Methicillin-resistant Staphylococcus aureus occurrence in long-term care facilities residents in Krakow, Poland. BMC Infectious Diseases, 14, 271. https://doi.org/10.1186/1471-2334-14-271
Simpson, R. J., Kunz, H., Agha, N., & Graff, R. (2015). Exercise and the Regulation of Immune Functions. Progress in Molecular Biology and Translational Science, 135, 355–380. https://doi.org/10.1016/bs.pmbts.2015.08.001
Spielmann, G., Bollard, C. M., Kunz, H., Hanley, P. J., & Simpson, R. J. (2016). A single exercise bout enhances the manufacture of viral-specific T-cells from  healthy donors: implications for allogeneic adoptive transfer immunotherapy. Scientific Reports, 6, 25852. https://doi.org/10.1038/srep25852
Turner, J. E. (2016). Is immunosenescence influenced by our lifetime “dose” of exercise? Biogerontology, 17(3), 581–602. https://doi.org/10.1007/s10522-016-9642-z
Walsh, N. P., & Oliver, S. J. (2016). Exercise, immune function and respiratory infection: An update on the influence of training and environmental stress. Immunology and Cell Biology, 94(2), 132–139. https://doi.org/10.1038/icb.2015.99
Warburton, D. E. R., & Bredin, S. S. D. (2017). Health benefits of physical activity: a systematic review of current systematic reviews. Current Opinion in Cardiology, 32(5), 541–556. https://doi.org/10.1097/HCO.0000000000000437
West, N. P., Pyne, D. B., Renshaw, G., & Cripps, A. W. (2006). Antimicrobial peptides and proteins, exercise and innate mucosal immunity. FEMS Immunology & Medical Microbiology, 48(3), 293–304. https://doi.org/10.1111/j.1574-695X.2006.00132.x
Zimmer, P., Schenk, A., Kieven, M., Holthaus, M., Lehmann, J., Lovenich, L., & Bloch, W. (2017). Exercise induced alterations in NK-cell cytotoxicity - methodological issues and  future perspectives. Exercise Immunology Review, 23, 66–81.

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