OPINION

Obesity and exercise immunology: implication in times of COVID-19 pandemic

Obesidade e imunologia do exercício: implicações em tempos de pandemia de COVI-19

 

Guilherme Gomes Azizi1,6, Marco Orsini2,3,4, Sérgio Duarte Dortas Júnior1,5, Sandro de Albuquerque Cerbino7

 

1Serviço de Imunologia, Hospital Universitário Clementino Fraga Filho (HUCFF-UFRJ)

2Universidade Iguaçu – UNIG

3Serviço de Neurologia/Neurocirurgia Universidade Federal Fluminense– UFF

4Universidade de Vassouras - USS

5Departamento de Clínica Médica- Universidade Federal do Rio de Janeiro- UFRJ

6Fluminense Football Club

7Serviço de Endocrinologia do Hospital Geral da Santa Casa de Misericórdia do Rio de Janeiro

 

Received on 2020 April 30; accepted 2020 May 2

Corresponding author: Guilherme Azizi, Rua Emílio Miranda, 28, 21211720 Rio de Janeiro RJ Brazil.

 

Guilherme Gomes Azizi: gazizi247@gmail.com

Marco Orsini: orsinimarco@hotmail.com

Sérgio Duarte Dortas Júnior: sdortasjr@gmail.com

Sandro de Albuquerque Cerbino: sandrocerbino@gmail.com

 

 

Obesity is a major worldwide epidemic, which places a burden on society and the public health system, affecting people of all ages and all social groups in developed and developing countries, reaching 650 million worldwide [1]. Thereby, we discuss the association between obesity inflammatory state and SARS-COV-2 infection, and the role of exercise immunology as a weapon and fundamental character to the health for million people in this pandemic time.

The current pandemic situation started with pneumonia patients with an unidentified cause emerged in Wuhan, Hubei Province, China, in December 2019 [2]. There about two months later the World Health Organization (WHO) announced a standard format of Coronavirus Disease-2019 (COVID-19) [3] on the same day was named as SARS-CoV-2 [4].

The SARS-CoV-2 was considered as a member of b-CoVs [5,6] like SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV) [7]. Therefore, COVID-19 demonstrated to be a predominant respiratory disease as an initial study presented 140 patients diagnosed, where the most common symptoms were fever (91.7%), cough (75%), fatigue (75%) and chest tightness or dyspnea (36.7%). However, 39.6% of them complained about gastrointestinal symptoms. 90 (64.3%) patients had comorbidity, the most common of which were chronic diseases, such as hypertension (30%) and diabetes (12.1%) [8].

Hypertension, diabetes, COPD, cardiovascular, cerebrovascular, liver, kidney, gastrointestinal diseases, in addition 60 years old, are factors relation susceptible to the infection by SARS-CoV-2 and experience higher mortality when they develop COVID-19 [9-11].

In SARS-CoV or MERS-CoV infection, there is an increased neutrophil and monocyte-macrophages influx in the severe cases [12,13]. All knowledge accumulated about previous coronavirus infections created a base to understand that innate immune response associated to cytokines plays a crucial role in antiviral responses and against coronavirus.

Increased cytokine levels (IL-6, IL-10, and TNF-α), lymphopenia (in CD4+ and CD8+ T cells), and decreased IFN-g expression in CD4+ T cells are associated with severe COVID-19 [14].  It seems that COVID-19 may have in “cytokine storm” a major role related to the involvement of IL-1, IL-6, IL-12, and TNF-α [15], creating a lung tissue damage resulting in ARDS, what can to carry to the organ failure. The risk of respiratory failure in patients with circulating IL-6 > 80 pg/ml was 22-fold higher with a median time to mechanical ventilation of 1.5 days [16].

A retrospective cohort investigated the association between body mass index (BMI) and clinical characteristics and the need for invasive mechanical ventilation in patients with SARS-CoV-2 attended in intensive care. The study reported a high frequency of obesity among patients admitted to intensive care for SARS-CoV-2. One hundred and twenty four patients (SARS-COV-2 positive) were admitted and included during the study. Median (IQR) BMI in SARS-CoV-2 participants was higher than in non SARS-CoV-2 controls; 29.6 (26.4 to 36.5) kg/m2 vs. 24.0 (18.9 to 29.3) kg/m2, respectively (p < 0.0001, t-test). 47.5% of subjects presented with obesity (BMI ≥ 30 kg/m2), including class II obesity (13.7%) and with class III obesity (14.5%). This distribution of BMI categories was markedly different subjects in intensive care for severe acute pulmonary condition (SARS-CoV-2 negative), which the prevalence of obesity was only 25.8% [17].

Overweight and obese adults have circulating levels of inflammatory cytokines, such as TNF-α and IL-6 [18-20], principally, due to the action of the fat cell that secretes other mediators as monocyte chemotactic protein 1 [21]. IL-6 and TNF-α induce insulin resistance [22,23], metabolic disorders and increased cardiovascular risk seen in obesity

All this inflammatory milieu seems to induce changes in innate immunity and acquired immunity, predisposing obese individuals to infection. NK cells are also quite influenced by leptin, either in its differentiation and proliferation, both in its activation and functionality. Leptin increases IL-2 production (promotes the proliferation and differentiation of cytotoxic T cells and stimulates NK cells) and the Th1 response (T helper 1), increasing the production of INF-g (stimulates the phagocytic response of macrophages) and TGF-b (transforming growth factor? transforming growth factor?), while inhibits the Th2 (T helper 2) response, that is, it will decrease the production of IL-4, IL-5, IL-6, IL-10, IL-13. Obese individuals have hyperleptinemia and studies in obese mice demonstrated that NK cells, monocytes and T cells develop resistance to leptin [24]. In addition, abdominal obesity is associated with impaired ventilation of the base of the lungs and consequently reduced oxygen saturation [20].

On the other hand, moderate-intensity exercise seems to increase immune response as also as decrease proinflammatory cytokine patterns. For instance, the EVASYON (Integral Education on Nutrition and Physical Activity for Overweight/Obese Adolescents) study, a program to promote a healthy lifestyle to weight lost, decreasing serum levels of leptin and IL-8, IL-10 and TNF-α [25]. Thus, lifestyle-aimed like exercise and adequate diet interventions can decrease the inflammatory condition.

A single bout dynamic exercise (minutes) increases the total leukocyte count two- to threefold. Exercise-induced leukocytosis mainly, neutrophils, lymphocytes, and monocytes are a transient phenomenon, with normal counts returning to preexercise levels (6-24 h) after exercise cessation. A rapid lymphocytopenia [26-28] occurs concomitantly with a sustained neutrophilia [26,29] 30–60 min after exercise cessation.

The innate cell's response to acute moderate-intensity exercise, can be demonstrated thought as the neutrophils that present phagocytosis enhanced immediately after a single exercise bout [30], as well chemotaxis [31]. After moderate intensity exercise cessation, the neutrophil oxidative burst continues to be enhanced, what is not true after exhaustive or prolonged exercise [32,33]. Other findings are related to well-trained athletes that are sensitive to the increases of training load, what present loss-making alterations in the neutrophil-monocyte oxidative burst, lymphocyte proliferation, and antibody synthesis, and NK-cell cytotoxic activity [34-38].

Furthermore, lower levels of circulating inflammatory cytokines [39], increased neutrophil phagocytic activity [40], greater NK-cell cytotoxic activity [41], indicate that regular moderate-intensity exercise can improve, or maintaining, immunity across the life [42].

An interesting point is IL-6 subtly increase during acute bouts of moderate-intensity exercise; what appears to provide protection, due to the pleiotropic nature,  to immunity via directly suppressing potent inflammatory cytokines [e.g., tumor necrosis factor alpha (TNF-α)] in the lungs, creating an anti-inflammatory milieu for several hours post-exercise [43].

Obesity is a worrisome epidemic that presents itself as one more factor to contribute to the COVID-19 severe cases. Physical Activity in secure ambient, an adequate diet, and all the suggestions of the authorities are attitudes that we need to follow. Regular exercise training of moderate intensity is believed to exert beneficial effects on immune function and in maintaining health. We sought we begin to clarify the importance of regular exercise of moderate intensity and the bad relation between obesity and COVID-19 complications.

 

References

 

  1. Mancini MC et al. Tratado de obesidade 2 ed. Rio de Janeiro: Guanabara Koogan; 2015.
  2. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY et al. Early transmission dynamics in Wuhan, China, of novel coronavirus–infected pneumonia. N Engl J Med 2020;382(13):1199-207. https://doi.org/10.1056/nejmoa2001316 
  3. World Health Organization Press Conference. The World Health Organization (WHO) has officially named the disease caused by the novel coronavirus as COVID-19. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen
  4. Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, Haagmans BL, Lauber C, Leontovich AM, Neuman BW et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses—A statement of the Coronavirus Study Group. Nature Microbiology https://doi.org/10.1038/s41564-020-0695-z
  5. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382(8):727-33. https://doi.org/10.1056/nejmoa2001017 
  6. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579(7798):270-3. https://doi.org/10.1038/s41586-020-2012-7 
  7. Weiss SR, Leibowitz JL. Coronavirus pathogenesis. Advance in virus research; 2011. p.85-164. https://doi.org/10.1016/b978-0-12-385885-6.00009-2 
  8. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, Akdis CA, D. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 27/02/2020. https://doi.org/10.1111/all.14238
  9. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and outcomes of 21 critically Ill patients with COVID-19 in Washington State. JAMA 2020;323(16):1612. https://doi.org/10.1001/jama.2020.4326
  10. Team TNCPERE. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) - China, 2020. China CDC Weekly 2020;2:113-22.
  11. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395(10229):1054-62. https://doi.org/10.1016/S0140-6736(1020)30566-30563
  12. Perlman S, Dandekar AA. Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol 2005;5(12):917-27. https://doi.org/10.1038/nri1732 
  13. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet 2015;386(9997):995-1007. https://doi.org/10.1016/s0140-6736(15)60454-8 
  14. Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest 2020;130(5):2202-5. https://doi.org/10.1172/jci137647 
  15. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033-4. https://doi.org/10.1016/s0140-6736(20)30628-0 
  16. Herold TVJ, Arnreich C, Hellmuth JC, von Bergwelt-Baildon M, Klein M, Weinberger T. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. medRxiv 2020. https://doi.org/10.1101/2020.04.01.20047381
  17. Simonnet A, Chetboun M, Poissy J et al. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation [published online ahead of print, 2020 Apr 9]. Obesity 2020. https://doi.org/10.1002/oby.22831
  18. Festa A, D’Agostino R Jr, Williams K et al. (2001) The relation of body fat mass and distribution to markers of chronic inflammation. Int J Obes Relat Metab Disord 2001;25:1407-15. https://doi.org/10.1038/sj.ijo.0801792 
  19.  Park HS, Park JY & Yu R. Relationship of obesity and viscera adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res Clin Pract 2005;69:29-35. https://doi.org/10.1016/j.diabres.2004.11.007 
  20. Bulló M, García-Lorda P, Megias I et al. Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res 2003;11:525-31. https://doi.org/10.1038/oby.2003.74 
  21. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347-55. https://doi.org/10.1079/bjn20041213 
  22. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006;444:860-7. https://doi.org/10.1038/nature05485 
  23. Bastard JP, Maachi M, Lagathu C et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006;17:4-12.
  24. Grenha AI et al. Obesidade e imunodepressão: Factos e números. Arq Med 2013;27(5):192-202.
  25. Romeo J, Martínez-Gómez D, Díaz LE et al. Changes in cardiometabolic risk factors, appetite-controlling hormones and cytokines after a treatment programme in overweight adolescents: preliminary findings from the EVASYON study. Pediatric Diabetes 2011;12:372-80. https://doi.org/10.1111/j.1399-5448.2010.00753.x 
  26. Walsh NP, Gleeson M, Shephard RJ et al. Position statement. Part one: immune function and exercise. Exerc Immunol Rev 2011;17:6-63.
  27. Campbell JP, Riddell NE, Burns VE et al. Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype. Brain Behav Immun 2009;23(6):767-75. https://doi.org/10.1016/j.bbi.2009.02.011 
  28. Simpson RJ, Florida-James GD, Whyte GP, Black JR, Ross JA, Guy K. Apoptosis does not contribute to the blood lymphocytopenia observed after intensive and downhill treadmill running in humans. Res Sports Med 2007;15(3):157-74. https://doi.org/10.1080/15438620701405339 
  29. Simpson RJ. The effects of exercise on blood leukocyte numbers. In: Gleeson M, Bishop NC, Walsh NP, eds. Exercise Immunology. Oxford, UK, New York, USA: Routledge; 2013. p.64-105. https://doi.org/10.4324/9780203126417 
  30. Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR et al. Effects of mode and carbohydrate on the granulocyte and monocyte response to intensive, prolonged exercise. J Appl Physiol 1998;84(4):1252-9. https://doi.org/10.1152/jappl.1998.84.4.1252 
  31. Ortega E, Collazos ME, Maynar M, Barriga C, De la Fuente M. Stimulation of the phagocytic function of neutrophils in sedentary men after acute moderate exercise. Eur J Appl Physiol Occup Physiol 1993;66(1):60-4. https://doi.org/10.1007/bf00863401 
  32. Bishop NC, Gleeson M, Nicholas CW, Ali A. Influence of carbohydrate supplementation on plasma cytokine and neutrophil degranulation responses to high intensity intermittent exercise. Int J Sport Nutr Exerc Metab 2002;12(2):145-56. https://doi.org/10.1123/ijsnem.12.2.145 
  33. Pyne DB. Regulation of neutrophil function during exercise. Sports Med 1994;17(4):245-58. https://doi.org/10.2165/00007256-199417040-00005 
  34. Gleeson M, McDonald WA, Cripps AW, Pyne DB, Clancy RL, Fricker PA. The effect on immunity of long-term intensive training in elite swimmers. Clin Exp Immunol 1995;102:210-6. https://doi.org/10.1111/j.1365-2249.1995.tb06658.x 
  35. Lancaster GI, Halson SL, Khan Q, Drysdale P, Jeukendrup AE, Drayson MT, Gleeson M. Effect of acute exhaustive exercise and a 6-day period of intensified training on immune function in cyclists. J Physiol 2003;548P:O96. https://www.physoc.org/abstracts/effect-of-acute-exhaustive-exercise-and-a-6-day-period-of-intensified-training-on-immune-function-in-cyclists/
  36. Lancaster GI, Halson SL, Khan Q, Drysdale P, Jeukendrup AE, Drayson MT, Gleeson M. The effects of acute exhaustive exercise and intensified training on type 1/type 2 T cell distribution and cytokine production. Exerc Immunol Rev 2004;10:91-106. https://www.ncbi.nlm.nih.gov/pubmed/15633589
  37. Robson PJ, Blannin AK, Walsh NP, Bishop NC, Gleeson M. The effect of an acute period of intense interval training on human neutrophil function and plasma glutamine in endurance-trained male runners. J Physiol 1999;515:84-5.
  38. Verde TJ, Thomas SG, Moore RW, Shek P, Shephard RJ. Immune responses and increased training of the elite athlete. J Appl Physiol 1992;73:1494-9. https://doi.org/10.1152/jappl.1992.73.4.1494 
  39. Yan H, Kuroiwa A, Tanaka H, Shindo M, Kiyonaga A, Nagayama A. Effect of moderate exercise on immune senescence in men. Eur J Appl Physiol 2001;86(2):105-11. https://doi.org/10.1007/s004210100521 
  40. Woods JA, Ceddia MA, Wolters BW, Evans JK, Lu Q, McAuley E. Effects of 6 months of moderate aerobic exercise training on immune function in the elderly. Mech Ageing Dev 1999;109(1):1-19. https://doi.org/10.1016/s0047-6374(99)00014-7 
  41. Simpson RJ, Lowder TW, Spielmann G, Bigley AB, Lavoy EC, Kunz H. Exercise and the aging immune system. Ageing Res Rev 2012;11:404-20.  https://doi.org/10.1016/j.arr.2012.03.003 
  42. ElKassar N, Gress RE. An overview of IL-7 biology and its use in immunotherapy. J Immunotoxicol 2010;7(1):1-7. https://doi.org/10.3109/15476910903453296 
  43. Dvorak J, Junge A, Derman W, Schwellnus M. Injuries and illnesses of football players during the 2010 FIFA World Cup. Br J Sports Med 2011;45(8):626-30. https://doi.org/10.1136/bjsm.2010.079905