COVID-19: A Tocsin to our Aging, Unfit, Corpulent, and Immunodeficient Society

Introduction

  The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) spread quickly to all parts of Earth during 2020 causing widespread morbidity and mortality. Intense scientific scrutiny during the first year of the COVID-19 pandemic has greatly broadened our understanding of SARS-CoV-2. This virus is highly transmissible through airborne droplets, with 40-45% of infections occurring in asymptomatic individuals that account for at least half of all known new cases (1,2). Although 80% of COVID-19 cases result in mild-to-moderate symptomatology, one in five develop significant symptoms. COVID-19 symptoms can persist for at least 6 months after acute infection, with fatigue, muscle weakness, sleep difficulties, anxiety and depression, and reductions in 6-minute walking test performance commonly reported by post-acute sequelae of SARS-CoV-2 infection (PASC), or “long COVID”, survivors (3,4). A considerable proportion (22-56% depending on disease severity) have pulmonary diffusion abnormalities at least 6 months after symptom onset (3).

  This review will emphasize that physical activity has potential value at each of the three prevention levels for COVID-19 (Figure 1). At the primary prevention level, several new epidemiological studies support that physical activity lowers the risk for COVID-19 (see Table 1). These data add to the growing awareness of physical activity’s role in improving immunosurveillance against pathogens and in lowering risk for a variety of respiratory infections. Secondary prevention strategies include vaccination. Although existing data are limited, some studies support that the immune response to vaccination is augmented in lean and fit individuals. At the tertiary prevention level, exercise rehabilitation has the potential to help PASC patients counter symptoms of fatigue and muscle weakness, similar to what has been reported for patients with chronic fatigue syndrome or those recovering from cancer treatment.

Primary Prevention: Physical Activity, Immunity, and COVID-19 Risk

  Mounting evidence supports a protective role of regular physical activity against a variety of respiratory infections (i.e., risk, incidence, severity, and mortality) (5-7). As summarized in Figure 2, risk for bacterial and viral infectious disease mortality was more than 50% lower as determined in a cohort of 97,844 adults followed for over nine years (8). Whether this protection extends to COVID-19 is currently an active area of scientific endeavor. Acute and chronic exercise has profound effects on immunosurveillance, as reviewed recently elsewhere (9,10).

  Demographic and lifestyle risk factors for severe illness from COVID-19 include older age, male sex, obesity (in all age groups), cigarette smoking, and underlying medical conditions (many of which are related to obesity) (11-14). Although physical inactivity has not yet been recognized by health agencies as a COVID-19 risk factors, mounting epidemiological evidence indicates an independent influence.

  As summarized in Table 1, several studies have been published using data from the UK Biobank (UKBB) prospective cohort. In one UKBB analysis, physical inactivity was related to a 32% increased risk for COVID-19 hospitalizations in 387,109 adults (8). Cigarette smoking (42% added risk) and obesity (105%) when combined with physical inactivity increased the risk of COVID-19 hospitalization 4.4-fold compared to optimal lifestyles. Unhealthy behaviors in combination accounted for up to 51% of the population attributable fraction of severe COVID-19 (8). In another UKBB analysis, higher levels of physical activity as measured with accelerometers was linked to a 20-26% reduced chance of being diagnosed with COVID-19 (15). In this same cohort, a poor balance between physical activity and sleep/rest was related to a 29% increased risk for severe COVID-19 (16). An additional UKBB analysis showed that low physical fitness (as measured by a slow walking pace) was strongly related to confirmed COVID-19 infection, and that obesity was a unifying risk factor (6). A retrospective observational study within the Henry Ford Medical Group showed an independent and inverse association between maximal exercise capacity and likelihood of COVID-19 hospitalization (17). In this study, the odds for COVID-19 hospitalization were 13% lower for every one MET higher level for exercise capacity measured during graded exercise tests.

  These are important data supporting the public health strategy of facilitating physical activity during the COVID-19 and future pandemics (18). Public health officials will debate the overall health impact of COVID-19 related social distancing measures for years to come. An analysis of 455,404 individuals from 187 countries showed that within 30 days of the COVID-19 pandemic declaration by the World Health Organization, mean step counts decreased 27.3% (19). This decrease in physical activity came during a time when regular physical activity was most needed. Physical activity has clear linkages to immune function and overall physical and mental health. Prolonged social distancing (at least not without guidance on how to maintain or increase physical activity) may not be the best public health strategy as we continue to battle current and future viral pandemics (12).

  Regular physical activity improves immunosurveillance against pathogens and reduces morbidity and mortality from viral infection and acute respiratory illness (9,10,12). Each 30-to-60-minute moderate-to-vigorous exercise bout improves overall surveillance against pathogens by stimulating the ongoing exchange of important types of white blood cells between the circulation and tissues. These immune cells that are activated and recruited during acute exercise bouts include neutrophils, macrophages, natural killer cells, cytotoxic T cells, and immature B cells. Over time, regular exercise-induced increases in antipathogenic leukocytes reduce infectious disease illness risk, and lower systemic inflammation. Thus, regular exercise training can be viewed as an immune system adjuvant and is of particular clinical value for obese individuals with comorbidities and older individuals. In a COVID-19 “call to action statement”, the American College of Sports Medicine (ACSM) recommended that individuals maintain immune health by participating in moderate physical activity 150-300 minutes per week and keeping body weight at normal levels (10).

  The immune system is broadly divided into the innate and adaptive arms, and have separate and linked tasks (20-22). The innate immune system functions as the first line of host defense against microbial infections (22). Innate immune signaling and inflammasome activation are well-established key barriers during viral infection. However, activation of the innate immune system must be tightly regulated, because excessive activation can lead to systemic inflammation and tissue damage. SARS-CoV-2 is unusually effective at evading the triggering of early innate immune responses by blocking type 1 interferons (IFNs), and this allows the virus to multiply quickly (20). The adaptive immune system is important for control of most viral infections including SARS-CoV-2 (20). The adaptive immune system consists of three major cell types: B cells, CD4+ T cells, and CD8+ T cells. B cells produce antibodies, CD8+ T cells excel in killing infected cells, and CD4+ T cells have helper and effector functions.

  The immune response to SARS-CoV-2 is summarized in Figure 3 for typical and severe COVID-19 cases (20). The magnitude of the antibody response against SARS-CoV-2 is highly heterogeneous between individuals (20). In a typical COVID-19 infection, SARS-CoV-2 infects cells by attaching to the viral entry receptor, ACE2, and is then recognized by pattern recognition receptors (23). In response, the innate immune system is activated, but the unique interferon (IFN)-blocking ability of SARS-CoV-2 (more so in men than women) allows the virus to multiply (21,23). Low IFN production from the innate immune system has been strongly associated with high SARS-CoV-2 viral burden and COVID-19 severity (20). The adaptive immune system’s T and B cells respond slowly (6-10 days) but vigorously, with an increase in SARS-CoV-2 specific antibodies, and ultimately a decrease in the viral load (20). Most SARS-CoV-2 infected individuals (90%) seroconvert by day 10 post-symptom onset (20).

  T cells, however, are dysfunctional in older and obese individuals with related comorbidities, and exhibit a dysregulated status of activation and function (21,23). Early in life, nearly all T lymphocytes express CD45RA, a typical marker of naïve cells that are more capable of responding to a novel pathogen such as SARS-CoV-2 (21). In contrast, older individuals have a higher proportion of memory versus naïve T cells, impairing the immune system’s capacity to clear SARS-CoV-2 (21).

  The adaptive immune response in these individuals is inadequate to stop the virus, and is compensated in part by an overactive innate immune response (20). As a result, the patient experiences excessive inflammation, tissue damage, high viral loads, and severe COVID-19 (20) (Figure 3). Immune changes linked to severe cases of COVID-19 include (20-26): 1) an increased ratio of neutrophils to lymphocytes (Ne/Ly); 2) elevated cytokines [interleukin (IL)-1β, IL-2R, IL-6, IL-8, IL-10, IL-15, IL-18, granulocyte-colony stimulating factor (GCSF), monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α]; 3) T cell dysregulation; 4) decreased lymphocyte counts for regulatory T cells (Tregs), CD4+ T cells, and CD8+ T cells; 5) a low lymphocyte-to-CRP ratio (LCR); and NLR family pyrin domain containing 3 (NLRP3) inflammasome activation (21). Most of these immune measures with severe COVID-19 are very similar in magnitude to those measured transiently in endurance athletes during recovery from competitive events (9). In the rested and uninfected state, lean and fit individuals have very low levels of systemic inflammation, low Ne/Ly and LCR, and strong innate and adaptive immunity responses, even in older age (9). The implication is that the immune systems in physically active, nonobese adults are less "primed" to respond in a negative fashion following SARS-CoV-2 infection.

  Much more remains to be learned about SARS-CoV-2, including issues related to pre-existing immunity from other coronaviruses, why immune responses and disease severity vary so widely between individuals, the potential for reinfection, vaccine elicited immunity and protection, how durable protection is over the long term, potency of variants, and how to improve immune memory (20).

Secondary Prevention: Physical Activity and COVID-19 Vaccination

  Building on years of basic science, several vaccines with high efficacy were developed within a year of the COVID-19 pandemic. The duration of immune memory and protective immunity in response to COVID-19 vaccines for varying demographic and lifestyle groups will be an active area of research for years to come.

  Obesity impairs the efficacy of the influenza vaccine, and the early concern was that the same finding would apply to COVID-19 vaccines. Initial results from the Pfizer-BioNTech and Moderna COVID-19 vaccine trials, however, indicated similar efficacy among individuals with and without obesity (27). Additional studies will provide data on long-term vaccine efficacy, particularly in high-risk groups.

  Although not conclusive, several studies indicate that acute or chronic exercise augments the antibody titer response to influenza vaccinations (28-33). Whether these data apply to COVID-19 vaccines remains to be determined. The most impressive data support that long-term exercise training improves the immune response to influenza vaccination. Four studies support that moderate exercise training by older adults enhances the mean fold increase in antibody titer after influenza immunization (30-33). One cross-sectional study, for example, of older adults showed that those exercising vigorously for 20 minutes per session three or more time per week had higher levels of influenza specific IgG and IgM compared to sedentary peers (33). T cell function as measured with peripheral blood mononuclear cell (PBMC) proliferation was highest in the vigorous exercise group, similar to findings from other studies (34).

  Influenza vaccination in athletes has been found to be safe and effective whether administered 2 hours or 24-26 hours after a training bout (35). One study showed that the increase in influenza virus specific T-cells and neutralizing antibodies was more pronounced in elite athletes compared to controls (36).

  Taken together, the data suggest that vaccine efficacy is positively related to a higher level of physical fitness through regular exercise training. Whether this applies to highly effective mRNA-based COVID-19 vaccines remains to be proven.

Physical Activity and Rehabilitation from COVID-19

  Ongoing studies indicate that morbidity of COVID-19 illness is prolonged with a significant symptom burden for many patients. The case definition for PASC has not yet been defined but is typically understood to be a collection of symptoms following COVID-19 that persist for more than 28 days (3,4). A survey of 3,762 respondents from 56 countries showed that the most common systemic symptoms were fatigue, post-exertional malaise (PEM), elevated temperature, chills/flushing/sweats, skin sensations, and weakness. Other common specific symptoms came from multiple organ systems and included sore throat, blurred vision, shortness of breath and dry cough, heart palpitations, tightness of chest, muscle aches, diarrhea, anxiety, irritability, depression, memory loss, headaches, balance issues, brain fog, sleep difficulties, and poor attention (4). Patients rated fatigue, breathing issues, and cognitive dysfunction as the most debilitating symptoms. Relapses were common and occurred in an irregular pattern, with exercise and mental stress as the main triggers. About two-thirds of respondents experienced symptoms for at least 6 months.

  Many of these symptoms are similar to myalgic encephalomyelitis, chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS) (37-39). PEM is one of the three required symptoms for ME/CFS, along with unrefreshing sleep and a reduction in ability to engage in pre-illness levels of activity. Of the respondents who experienced PEM (89%), about half experienced it immediately after exercise or the same day, and the other half the following 1 to 3 days (38).

  ME/CFS is a debilitating disorder that affects up to 2.5 million Americans. Infections from viruses, and immunologic and endocrine disorders may be underlying causes for ME/CFS (38,39). No effective treatment has been approved for patients with ME/CFS, but cognitive behavior therapy and graded exercise therapy are typically recommended as effective therapies for ME/CFS (37). Physical activity with a gradual increase in intensity is recommended for ME/CFS and long COVID, but with care to avoid a worsening of symptoms.

  Evidence-based recommendations for return-to-exercise guidelines are limited, but rest and no exercise for two weeks from a positive COVID-19 test result is encouraged under the guidance of a health care team. A slow resumption of exercise training is then recommended with close monitoring for clinical deterioration. This is a conservative approach until more is known about the interaction between SARS-CoV-2, heavy exertion, and heart health (10,12,40).

  A critical concern for highly active individuals and competitive athletes is the potential for cardiac injury from SARS-CoV-2 (41,42). Acute cardiac injury and myocarditis have been observed in a significant proportion of hospitalized patients with COVID-19, and exercise could accelerate viral replication and cardiac damage. There is increasing concern that athletes may be susceptible to COVID-19-induced myocarditis. Emerging data support COVID-19-induced cardiac injury in non-athletes in the general community. At present, there are insufficient data to support cardiac magnetic resonance imaging (CMR) of all athletes. CMR is appropriate when clinical symptoms and objective pathologic criteria are suggestive of myocarditis (41).

Conclusions

  This article emphasized that physical activity has potential benefits to counter COVID-19 infection at three prevention levels. Several epidemiological studies support that regular physical activity is associated with a reduced risk for COVID-19. Although specific COVID-19 related studies are needed, data from studies with other types of infectious agents support the potential role for physical activity to augment COVID-19 vaccine efficacy and to improve the quality of life for PACS patients.

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Healthy, high level athletes were given the influenza vaccine within 2 or 24-26 hours after the last training session. Both groups experienced similar increases in influenza specific antibodies and CD4 T cells.

36. Ledo A, Schub D, Ziller C, Enders M, Stenger T, Gärtner BC, Schmidt T, Meyer T, Sester M. Elite athletes on regular training show more pronounced induction of vaccine-specific T-cells and antibodies after tetravalent influenza vaccination than controls. Brain Behav Immun. 2020 Jan;83:135-145. PMID: 31580932.

High-level athletes and controls received the influenza vaccine, and the athletes experienced a more pronounced increase in influenza-specific T cells and neutralizing antibodies.

37. Kim DY, Lee JS, Park SY, Kim SJ, Son CG. Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med. 2020 Jan 6;18(1):7. PMID: 31906979.

This systematic review showed therapeutic support for CFS/ME for non-pharmacological therapies including cognitive-behavior-therapy-related treatments and graded-exercise-related therapies.

38. Joseph P, Arevalo C, Oliveira RKF, Faria-Urbina M, Felsenstein D, Oaklander AL, Systrom DM. Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Chest. 2021 Feb 9:S0012-3692(21)00256-7. PMID: 33577778.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide, but the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia. , and objective evidence of small fiber neuropathy (SFN) is reported in ∼50% of POTS and fibromyalgia patients. During exercise, ME/CFS patients averaged lower right atrial pressures and peak VO2 than controls.

39. Nacul L, O'Boyle S, Palla L, Nacul FE, Mudie K, Kingdon CC, Cliff JM, Clark TG, Dockrell HM, Lacerda EM. How Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Progresses: The Natural History of ME/CFS. Front Neurol. 2020 Aug 11;11:826. PMID: 32849252.

As in other chronic diseases, ME/CFS evolves through different stages, from asymptomatic predisposition, progressing to a prodromal stage, and then to symptomatic disease. Disease incidence depends on genetic makeup and environment factors, the exposure to singular or repeated insults, and the nature of the host response.

40. Phelan D, Kim JH, Chung EH. A Game Plan for the Resumption of Sport and Exercise After Coronavirus Disease 2019 (COVID-19) Infection. JAMA Cardiol. 2020 May 13. PMID: 32402054.

For athletes who remain asymptomatic and are negative for COVID-19, return to exercise training is permissible without additional testing. However, asymptomatic athletes who test positive for COVID-19 antigen (active infection) should refrain from exercise training for at least 2 weeks from the date of positive test result and follow strict isolation guidelines. If athletes remain asymptomatic, slow resumption of activity should be guided under direction from their medical professional.

41. Kim JH, Levine BD, Phelan D, Emery MS, Martinez MW, Chung EH, Thompson PD, Baggish AL. Coronavirus Disease 2019 and the Athletic Heart: Emerging Perspectives on Pathology, Risks, and Return to Play. JAMA Cardiol. 2021 Feb 1;6(2):219-227. PMID: 33104154.

Cardiac injury with attendant negative prognostic implications is common among patients hospitalized with coronavirus disease 2019 (COVID-19) infection. Whether cardiac injury, including myocarditis, also occurs with asymptomatic or mild-severity COVID-19 infection is uncertain. There is an ongoing concern about COVID-19-associated cardiac pathology among athletes because myocarditis is an important cause of sudden cardiac death during exercise.

42. Phelan D, Kim JH, Elliott MD, Wasfy MM, Cremer P, Johri AM, Emery MS, Sengupta PP, Sharma S, Martinez MW, La Gerche A. Screening of Potential Cardiac Involvement in Competitive Athletes Recovering From COVID-19: An Expert Consensus Statement. JACC Cardiovasc Imaging. 2020 Dec;13(12):2635-2652. PMID: 33303102.

This review seeks to evaluate the current evidence regarding COVID-19-associated cardiovascular disease and how multimodality imaging may be useful in the screening and clinical evaluation of athletes with suspected cardiovascular complications of infection.

Additional reading: Nalbandian, A., Sehgal, K., Gupta, A. et al. Post-acute COVID-19 syndrome. Nat Med (2021). https://doi.org/10.1038/s41591-021-01283-z

Table 1 Epidemiological research on the relationship between physical activity, physical fitness, and COVID-19 outcomes.

Investigators, year published	Study population	Research and statistical design	Key findings
Zhang et al., 2020 (15)	>Prospective cohort, 500,000 adults, United Kingdom Biobank (UKBB) study; 1,746 with COVID-19 (age 68.8±9.2 y, 399 deaths (age 74.7±6.0).	Logistic regression analysis of physical activity (PA) (objectively, subjectively measured) and COVID-19 outcomes; test of causality using Mendelian randomization (MR).	Protective effect (20-26%) of objectively measured PA on COVID-19 outcomes after adjustment (age, sex, obesity, smoking). MR analyses did not support a causal association.
Brawner et al., (17)	246 patients (age, 59±12 y; 42% male; 75% black race) with maximal exercise capacity test, positive for SARS-CoV-2.	Logistic regression, COVID-19 hospitalization and peak metabolic equivalents (METs), with adjustment for 13 covariates.	Peak METs lower (P<.001) among hospitalized patients (6.7±2.8) vs. not hospitalized (8.0±2.4) (odds ratio, OR, adjusted model, 0.87).
Hamer et al., (8)	Prospective cohort of 387,109 adults, UKBB study, ages 40-69 y.	Regression models fitted to estimate RR for associations between physical activity, obesity, smoking, and alcohol consumption (baseline questionnaires) and severe COVID-19.	RRs adjusted for age, sex and each lifestyle factor were raised for physical inactivity (1.32), smoking (1.42), and obesity (2.05), but not heavy alcohol intake (1.12).
Ho et al., 2020 (6)	Prospective cohort, 235,928 adults (age 49-83 y), UKBB study tested for SARS-CoV-2; 397 with confirmed COVID-19.	Poisson regression of self-reported slow walking pace (fitness), demographic and modifiable risk factors for COVID-19 (relative risk, RR).	Slow walking pace linked to COVID-19 diagnosis (RR 1.53) after multivariable adjustment; BMI (RR 1.29), smoking (RR 1.39).
Rowlands et al., (16)	Prospective cohort of 91,248 adults (age 49-83 y), UKBB study, 207 with confirmed COVID-19, 124 severe.	Logistic regression, severe COVID-19 with physical activity (accelerometer data) and sleep/rest variables, with adjustment for age, sex, ethnicity, diet, smoking, and other factors.	Higher daytime activity related to lower risk for severe COVID-19 (OR=0.75). Higher movement during sleep/rest linked to higher risk (OR=1.26). Proper balance of activity and sleep/rest linked to a 30% lower risk of severe COVID-19.
Zhang et al., 2020 (15)	>Prospective cohort, 500,000 adults, United Kingdom Biobank (UKBB) study; 1,746 with COVID-19 (age 68.8±9.2 y, 399 deaths (age 74.7±6.0).	Logistic regression analysis of physical activity (PA) (objectively, subjectively measured) and COVID-19 outcomes; test of causality using Mendelian randomization (MR).	Protective effect (20-26%) of objectively measured PA on COVID-19 outcomes after adjustment (age, sex, obesity, smoking). MR analyses did not support a causal association.

Figure 1. Physical activity has a role in combating COVID-19 morbidity and mortality at each prevention level. Regular physical activity lowers the risk for severe COVID-19, may augment the antibody response to COVID-19 vaccinations, and is projected to improve rehabilitation for PACS (long COVID-19) patients.



Figure 2. Protective role of regular physical activity against respiratory infections. Risk for bacterial and viral infectious disease mortality was more than 50% lower as determined in a cohort of 97,844 adults followed for over nine years (8).



Figure 3. Immune responses of individuals with typical (A) compared to severe (B) COVID-19. SARS-CoV-2 is unusually effective in evading the activation of early innate immune responses (e.g., IFNs), and the virus can multiply more quickly before triggering an appropriate adaptive immune response. In a typical COVID-19 infection, the innate immune system responds early and strongly to SARS-CoV-2 and primes T cells from the adaptive immune system to reduce the viral load. This response, however, can be atypical and amplified with age because of a smaller naïve T cell pool, and with obesity because of dysfunctional T cells. The innate response may be excessive (in response to diminished adaptive immunity) leading to high levels of inflammation and damage in multiple tissues including the lungs (20).