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The Emerging Role of Exercise and Optimal Exercise Prescription for Improving the Symptoms of Long COVID
Korean J Sports Med 2023;41:119-129
Published online September 1, 2023;  https://doi.org/10.5763/kjsm.2023.41.3.119
© 2023 The Korean Society of Sports Medicine.

Tae Gu Choi1,*, Jae Yeop Kim1,*, Setor K Kunutsor2, Sae Young Jae1,3,4

1Department of Sport Science, University of Seoul, Seoul, Korea, 2Diabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK, 3Division of Urban Social Health, Graduate School of Urban Public Health, University of Seoul, Seoul, 4Department of Urban Big Data Convergence, University of Seoul, Seoul, Korea
Correspondence to: Sae Young Jae
Department of Sport Science, University of Seoul, 163 Seoulsiripdae-ro, Dongdaemun-gu, Seoul 02504, Korea
Tel: +82-2-6490-2953, Fax: +82-2-6490-2949
E-mail: syjae@uos.ac.kr
*These authors contributed equally to this work as co-first authors of this manuscript.
Received June 30, 2023; Revised August 17, 2023; Accepted August 18, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Long COVID has emerged as a global medical challenge, characterized by persistent symptoms such as fatigue, dyspnea, and exercise intolerance following a coronavirus disease 19 (COVID-19) infection. The protracted nature of these symptoms necessitates the development of effective therapeutic approaches to alleviate the burden on individuals’ well-being and the healthcare system at large. While current pharmacological interventions offer limited efficacy, the exploration of alternative strategies becomes imperative. Exercise training has demonstrated promise in ameliorating long COVID symptoms, yet consensus regarding the optimal exercise modalities remains elusive. In light of this, the present review aims to elucidate the impact of exercise on long COVID symptoms and shed light on exercise prescriptions that have exhibited proven efficacy in the treatment and management of this syndrome.
Keywords : Post-acute COVID-19 syndrome, Long COVID, Exercise, Rehabilitation
Introduction

Long COVID, also known as post-acute sequelae of coronavirus disease 2019 (COVID-19), has recently surfaced as a significant global health concern. It manifests as a range of persistent symptoms, including fatigue, dyspnea, and exercise intolerance, among others, thereby imposing a considerable burden on individuals’ health and the healthcare system beyond the initial COVID-19 infection. Consequently, there is a pressing need for effective therapeutic strategies that can ameliorate long COVID symptoms and alleviate the strain on personal well-being and healthcare resources. Regrettably, currently available pharmacological interventions have exhibited limited efficacy, necessitating the exploration of alternative approaches. Intriguingly, emerging evidence suggests that exercise training may hold promise as an alternative strategy to improve long COVID symptoms. However, the lack of consensus regarding the most effective exercise methods remains a challenge. This review aims to provide an overview of the current understanding of the impact of exercise on long COVID symptoms and, where applicable, highlight findings from exercise prescriptions that have demonstrated efficacy in treating and managing this clinical syndrome.

Methods

To gather evidence on the health benefits of exercise for long COVID, an electronic literature review was conducted using a combination of relevant keywords: “physical activity,” “exercise training,” “cardiopulmonary fitness,” “COVID-19,” “lifestyle factors,” “long COVID,” “post-acute COVID-19 condition,” and “structured exercise.” The search was limited to articles published in English, in peer-reviewed journals indexed on Google Scholar, PubMed, and Web of Science, spanning from December 2019 to June 2023. The eligibility criteria were determined based on the PICO (Population, Intervention, Comparison, and Outcomes) framework, incorporating the following parameters: (1) Population: individuals worldwide with long COVID, (2) Intervention: studies evaluating the effects of aerobic, resistance, and/or respiratory exercise training on long COVID patients, (3) Comparison: pre-post intervention measurements, and (4) Outcome: assessments of long COVID symptoms (e.g., dyspnea, fatigue, anxiety, and depression) and objective measures of physical function (e.g., pulmonary function, vascular function, and exercise capacity). Studies that did not provide specific information on exercise prescriptions were excluded. In total, 48 potentially relevant clinical trials or randomized clinical trials were identified from the databases. Two authors independently screened each title and abstract based on the eligibility criteria, resulting in 36 studies being considered eligible. The selected studies underwent a thorough full-text review, and ultimately, 12 studies were included in the current synthesis of exercise prescription for long COVID in our study. A flow chart depicting the literature search process and study selection on exercise prescription and long COVID outcomes can be found in Fig. 1.

Fig. 1. Flow chart of literature search on exercise prescription and post-acute sequelae of coronavirus disease 2019 (long COVID) outcomes.
Overview of Long COVID

World Health Organization (WHO) conducted a Delphi consensus process and designated this condition as “post COVID-19 condition” or “long COVID.” The WHO defines long COVID as the presence of symptoms persisting for more than 2 months following a possible or confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with these symptoms not being explained by other diagnoses for at least 3 months after the infection1.

A comprehensive meta-analysis encompassing 41 studies conducted across various countries revealed that the global prevalence of long COVID is estimated to be 43%2. Long COVID is characterized by a diverse array of postinfectious symptoms, including fatigue, dyspnea, cognitive impairment, depression, and anxiety3-5. Among the reported symptoms, fatigue emerged as the most common, followed by memory problems and dyspnea2. Persistence of long COVID varies from 3 months to more than 6 months or more, demonstrating heterogeneity among the studies6-8. Fig. 2 illustrates the continuum of long COVID and its associated persistent symptoms.

Fig. 2. Continuum post-acute sequelae of coronavirus disease 2019 (long COVID) and its associated persistent symptoms.

Several risk factors associated with long COVID have been identified, including the severity of acute illness during the initial COVID-19 infection and the presence of underlying health conditions2,9. Studies have indicated that the incidence of long COVID is higher in individuals who experienced a more severe form of COVID-192. Furthermore, patients who received inpatient treatment for COVID-19 have shown a higher incidence of long COVID compared to those who received outpatient care. Demographically, women have been found to be at a higher risk of developing long COVID than men, and the incidence of long COVID tends to increase with age10. However, it should be noted that some studies have reported cases of long COVID occurring in those with mild severity of the initial COVID-19 or younger age11,12, suggesting long COVID can potentially affect anyone who has been infected with COVID-1913.

The precise mechanisms underlying long COVID have yet to be fully elucidated, but several theories have been proposed. Firstly, it is believed that SARS-CoV-2, the virus responsible for COVID-19, may persist in the body following the acute infection, leading to chronic inflammation and contributing to the development of long COVID14. Secondly, continuous exposure to the virus, persisting beyond the acute phase, may result in immune exhaustion, impairing the clearance of the virus and perpetuating chronic inflammation, thereby contributing to long COVID14. Thirdly, it has been suggested that SARS-CoV-2–specific antibodies may trigger excessive immune reactions that contribute to long COVID symptoms15. In addition, persistence of the virus may induce virus-mediated down-regulation of angiotensin-converting enzyme leading to imbalances in the renin-angiotensin system which can be responsible for the development of long COVID16.

Given the uncertain pathophysiology that affects various body systems, there is currently no definitive treatment approach for long COVID. Pharmacological interventions have shown limited effectiveness, and the current approach primarily focuses on regular monitoring and symptom management17,18. As a result, there is a growing recognition of the need for multidisciplinary research and comprehensive strategies, including nonpharmacological treatments, to effectively manage and improve long COVID19.

The complex nature of long COVID requires a holistic approach that encompasses various aspects of patient care, such as physical rehabilitation, psychological support, and symptom management. Nonpharmacological interventions, including exercise therapy, cognitive-behavioral therapy, and supportive care, are being explored as potential avenues to address the diverse symptoms and improve the overall well-being of long COVID patients.

Beneficial Effects of Exercise in Long COVID

Exercise plays a crucial role in improving physical fitness, which is closely linked to overall health and well-being20,21. One of the advantages of exercise is that it can provide similar benefits to medication without the associated side effects, reducing the incidence of diseases and mortality rates22,23. Moreover, regular exercise has been found to decrease the risk of severe and fatal infections related to COVID-1924. As such, exercise holds the potential to improve long COVID symptoms while enhancing physical function and fitness, aiding in the recovery process to attain a pre-COVID health state25.

Notably, several organizations and guidelines, including the WHO, recommend exercise and physical therapy as part of the management approach for long COVID26,27. Recent studies have also reported the effectiveness of exercise interventions in improving long COVID symptoms, both within institutional settings and at the community level28,29. However, it is important to acknowledge the wide variation and lack of standardization in the interventions employed across these studies. Therefore, the following section will provide a comprehensive summary of the efficacy of exercise in alleviating various long COVID symptoms and discuss the exercise prescriptions utilized in the reviewed studies. The effects of exercise on enhancing physical function and improving long COVID symptoms will be synthesized and presented in Table 1 and Fig. 3, based on the current findings reported in the literature.

Table 1 . Summary of studies on outcomes of exercise on long COVID symptoms and physical function

StudyYearNo. of subjectsTraining duration (wk)Result
Del Valle et al.552022208Exertional dyspnea and fatigue ↓
Exercise capacity (6MWD) ↑
Cardiac function (HRR) ↑
Hayden et al.5120211083Dyspnea (mMRC, NRS) ↓
Fatigue (BFI) ↓
Anxiety (GAD-7) ↓
Depression (PHQ-9) ↓
Exercise capacity (6MWD) ↑
Quality of life (EQ5D5L) ↑
Hockele et al.572022298Dyspnea (mMRC) ↓
Functional status (PCFS) ↑
Exercise capacity (6MWD) ↑
Physical function (TUGT) ↑
Pulmonary function (FVC, FEV1, MIP, MEP) ↑
Nopp et al.532022586Dyspnea (mMRC) ↓
Exertional dyspnea (Borg dyspnea) ↓
Fatigue (FAS) ↓
Functional status (PCFS) ↑
Exercise capacity (6MWD) ↑
Pulmonary function (FEV1, DLCO, MIP) ↑
Quality of life (EQ5D) ↑

Long COVID: post-acute sequelae of coronavirus disease 2019, 6MWD: 6-minute walking distance, HRR: heart rate recovery, mMRC: modified medical research council dyspnea scale, NRS: numeric rating scale, BFI: brief fatigue inventory, GAD-7: generalized anxiety disorder-7, PHQ-9: patient health questionnaire-9, EQ5D5L: Euro-quality of life-5 dimension 5 level, PCFS: post-COVID functional status, TUGT: timed up and go test, FVC: forced voluntary capacity, FEV1: 1 second-forced expiratory volume, MIP: maximal inspiratory pressure, MEP: maximal expiratory pressure, FAS: fatigue assessment scale, DLCO: diffusion capacity of lung for carbon dioxide, EQ5D: Euro-quality of life-5 dimension.


Fig. 3. Beneficial effects on exercise on improving post-acute sequelae of COVID-19 (long COVID) symptoms and physical function. COVID-19: coronavirus disease 2019.

Fatigue is a prevalent symptom of long COVID, and it can have a significant impact on daily activities and overall quality of life30-32. Studies have indicated that exercise regimens can lead to improvements in fatigue and exercise tolerance among individuals with long COVID. A study involving aerobic and resistance training conducted three times a week for 8 weeks showed significant improvements in fatigue and exercise tolerance in a group of 19 long COVID patients33. Similarly, another study incorporating aerobic and resistance training three times a week for 8 weeks demonstrated notable reductions in fatigue and improvements in physical function among 40 long COVID patients34. Furthermore, remote breathing exercises performed three times a week for 6 weeks effectively enhanced fatigue level and daily activity performance in 71 long COVID patients35. These findings highlight the potential of exercise interventions to alleviate fatigue and enhance physical function in long COVID patients.

Dyspnea, characterized by a subjective discomfort during breathing, is a prominent symptom in long COVID and is often associated with pulmonary function impairment36,37. Previous research has demonstrated the effectiveness of exercise interventions in improving dyspnea and pulmonary function in long COVID patients. For instance, a study involving inspiratory muscle training using a handheld inspiratory resistance device three times a week for 8 weeks showed significant improvements in dyspnea and pulmonary function in a cohort of 111 long COVID patients38. Also, a 2-month program consisting of aerobic and resistance training performed three times a week by 39 long COVID patients resulted in significant enhancements in exercise tolerance and exertional dyspnea39. Additionally, a systematic review investigating exercise-based pulmonary rehabilitation programs, including aerobic and resistance training, for individuals experiencing dyspnea following COVID-19 infection, reported that exercise interventions improved dyspnea and respiratory function, including physical fitness, in long COVID patients29,40. These findings emphasize the potential of exercise in alleviating dyspnea symptoms and improving respiratory function in long COVID.

Long COVID is associated with cognitive symptoms such as brain fog, decreased concentration, as well as mental health symptoms including depression and anxiety41. These symptoms can have a profound impact on daily life and reduce overall quality of life42. Previous research has indicated the potential benefits of exercise in improving cognitive function and alleviating mental health symptoms in individuals with long COVID. Such as a study involving 32 individuals with long COVID showed significant improvements in cognitive function and a trend towards reduced symptoms of depression and anxiety after engaging in aerobic and resistance training twice a week for 6 weeks43. Similarly, a study involving 30 long COVID patients demonstrated that a combination of aerobic and resistance training conducted three times a week for approximately 4 weeks led to significant improvements in symptoms of depression and anxiety, as well as overall quality of life44. Another study involving 44 individuals with long COVID reported significant improvements in cognitive function and symptoms of depression and anxiety after an eight-week breathing exercise program conducted six times a week45. These findings suggest that exercise interventions can be beneficial in improving cognitive function and alleviating symptoms of depression and anxiety in individuals with long COVID, thus potentially enhancing mental well-being and overall quality of life.

Studies have demonstrated a significant decline in cardiorespiratory fitness (CRF) among individuals with long COVID symptoms46. Assessing CRF through a cardiopulmonary exercise test (CPET) can provide an objective evaluation of an individual’s health status and fitness level, offering valuable diagnostic information for individuals with long COVID47. In line with this, the American College of Cardiology recommends CPET as a means to evaluate long COVID and facilitate safe physical activity and return to daily life48. Having low CRF, measured by CPET, is associated with an increased incidence and mortality risk of cardiovascular diseases49. Therefore, improving CRF in individuals with long COVID is an important consideration.

Previous studies have shown that aerobic and resistance training performed three times a week for 8 weeks can lead to significant improvements in CRF among individuals with long COVID symptoms who did not reach the predicted maximum exercise capacity33,50. Similarly, other studies have demonstrated significant improvements in physical function, including CRF, after 12 weeks of aerobic and resistance training performed three times a week among individuals with similar conditions51. These findings highlight the potential of exercise interventions in enhancing CRF and overall physical function in individuals with long COVID.

Exercise Prescription for Improving Long COVID Symptoms

Exercise has emerged as a promising intervention for alleviating long COVID symptoms and enhancing overall physical well-being, as well as improving CRF. However, it is essential to consider individualized exercise prescriptions and consult healthcare professionals to ensure the safe and appropriate implementation of exercise interventions tailored to each patient’s unique circumstances and capabilities. Thus, the implementation of a comprehensive exercise program that incorporates aerobic, resistance, and respiratory exercise holds great potential in effectively managing and ameliorating long COVID. By meticulously reviewing and synthesizing prior studies that have prescribed successful aerobic, resistance, and respiratory exercise interventions targeting long COVID symptoms and physical function (as outlined in Table 2), our objective is to propose a well-defined exercise program comprising appropriate frequency, intensity, exercise modality, and duration to optimize long COVID management and improvement.

Table 2 . Exercise intervention characteristics of reviewed studies

StudyYearFrequency (days/wk)Duration (wk)IntensityTimeType
Barbara et al.49202238LT 80%30닋60 minAerobic exercise
1RM 40%12 repetitions, 2닋3 setsResistance exercise (large muscle group)
Hayden et al.5120213닋53Borg scale 463060 minAerobic exercise
2닋33-12 repetitions, 3 setsResistance exercise (large muscle group)
73-21 minRespiratory exercise
Jimeno-Almaz찼n et al.33202238HRR 55%닋80%30닋60 minAerobic exercise
1RM 50%8 repetitions, 3 sets, 4 exercisesResistance exercise
Jimeno-Almaz찼n et al.54202338HRR 55%닋80%30닋60 minAerobic exercise
MIP 60%30 repetitions, 2 setsRespiratory exercise (handheld inspiratory muscle trainer)
1RM 50%8 repetitions, 3 setsResistance exercise
Palau et al.582022712MIP 25%닋30%20 min, 2 sessions/dayRespiratory exercise (handheld inspiratory muscle trainer)

LT: lactate threshold, 1RM: one repetition maximum, HRR: heart rate reserve, MIP: maximal inspiratory pressure.



1. Aerobic exercise

Numerous studies have examined the application of aerobic exercise in individuals with long COVID, with the most common methods involving the use of a treadmill or stationary bicycle33,50-55. These studies have employed different approaches to determine exercise intensity, primarily utilizing either heart rate or the subjective rate of perceived exertion (RPE). When heart rate was used as the basis for intensity, moderate to vigorous-intensity aerobic exercise was prescribed, targeting 50% to 70% of the heart rate reserve. Alternatively, when RPE (Borg 10) was employed, a moderate-intensity aerobic exercise was set at 4 to 6 points on the scale. The duration of aerobic exercise was predominantly set at 30 minutes across the reviewed studies. Based on the collective findings, engaging in aerobic exercise at a moderate intensity or higher for a duration of 30 minutes has demonstrated effectiveness in improving both long COVID symptoms and overall physical function.

2. Resistance exercise

Several previous studies have investigated the inclusion of weight machines, barbell, and dumbbell exercises to determine specific exercise intensities for resistance training in individuals with long COVID33,50,54,55. The intensity of the load used in resistance exercise was expressed as a percentage of one repetition maximum (1RM) and varied between 30% and 80%. Most studies initiated the resistance training at 40% to 50% of 1RM and progressively increased the load, performing 8 to 12 repetitions until muscle exhaustion. In cases where information on 1RM was not provided, the studies indicated that a weight allowing for 10 to 12 repetitions maximum was utilized. The resistance exercise protocols typically comprised four to 10 different exercises targeting major muscle groups such as the chest, back, and legs, and were performed in two or three sets. Based on the findings of previous studies, it has been demonstrated that resistance exercise programs consisting of a load at 40% to 50% of 1RM, encompassing four or more exercises targeting major muscle groups, and involving two or three sets are effective for improving long COVID symptoms and physical function.

3. Respiratory exercise

Respiratory exercises, including diaphragmatic breathing and inspiratory muscle training using a handheld respiratory muscle training device, have demonstrated effectiveness in improving symptoms of long COVID and pulmonary function according to previous studies52,54-59. These exercises are widely recommended as a rehabilitation exercise method by esteemed organizations such as the American Thoracic Society and the European Respiratory Society60. However, the isolated effects of diaphragmatic breathing, which involves placing a weight on the abdomen while lying down and focusing on diaphragmatic use during 30 breaths, cannot be definitively assessed as it is often performed in combination with other breathing exercises. Consequently, it can be concluded that inspiratory muscle training using a handheld respiratory muscle training device, set at an intensity of 30% to 50% of the maximum inspiratory pressure, and performed for 30 breaths in one or two sets, represents an effective respiratory exercise regimen for improving symptoms associated with long COVID.

Based on the effective aerobic, resistance, respiratory exercise prescription and methods from previous studies, Table 3 proposes an exercise program to improve long COVID symptoms. The exercise program is comprised of continuous aerobic, resistance, respiratory exercises for about 1 hour and each exercise’s frequency, intensity, type, and time were set considering the feasibility. The exercise program is recommended to be done at least three times a week and a gradual increase in exercise intensity should be considered.

Table 3 . Exercise prescription for improving the symptoms of long COVID

TypeMethodIntensityTime (min)
Aerobic exerciseTreadmill
Stationary cycle
HRR 50%닋60%30
Resistance exerciseResistance training machine or dumbbell/barbell exercise that includes large muscle group (chest, back, leg)1RM 40%닋50%, 10닋12 repetition, 2 sets, 4 exercises20
Respiratory exerciseInspiratory muscle exerciseMIP 40%닋50%, 10 repetitive breaths, 3 sets10

Long COVID: post-acute sequelae of coronavirus disease 2019, HRR: heart rate reserve, 1RM: one repetition maximum, MIP: maximal inspiratory pressure.


Does Exercise Worsen Symptoms of Long COVID?

Post-exertional malaise (PEM) is a significant symptom observed in individuals with long COVID, manifesting as an exacerbation of symptoms following physical exertion61. This phenomenon shares similarities with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), wherein symptoms intensify after engaging in physical, emotional, or mental activities62. Notably, there have been concerns raised regarding proposed exercise trials for long COVID63. Few studies have reported that physical activity worsened symptoms or lead to relapses in individuals with long COVID8,64. For example, one study found that 75% of adults with long COVID experienced worsened symptoms after a bout of exercise8. However, there is limited research specifically confirming the effectiveness of exercise training in alleviating PEM in individuals with long COVID, although exercise therapy is commonly employed in managing ME/CFS and holds potential as a treatment option for PEM65. Nonetheless, prior to initiating an exercise program, it is crucial to screen for PEM and closely monitor symptom exacerbation in response to exertion to ensure safety and feasibility66. Further interventional studies are needed to establish the potential benefits or risks of exercise in improving PEM in individuals with long COVID.

Conclusions

An integrated exercise program comprising aerobic, resistance, and respiratory exercises has been proposed as an effective strategy to improve symptoms associated with long COVID. This comprehensive program is expected to have a notable impact on key manifestations of long COVID, including fatigue, dyspnea, cognitive impairment, depression, and anxiety, while also addressing the broader range of physical impairments resulting from the condition. By implementing such an exercise program, it is anticipated that significant strides can be made in addressing the public health challenge posed by long COVID, facilitating symptom improvement, and supporting individuals in regaining their pre–COVID-19 level of health and functioning. Nevertheless, there are still symptoms for which the efficacy of exercise intervention remains unconfirmed as depicted in Fig. 3, necessitating further studies to investigate the effect of exercise interventions on various long COVID symptoms.

Conflict of Interest
Sae Young Jae is the Editor-in-Chief of The Korean Journal of Sports Medicine and was not involved in the review process of this article. All authors have no other conflicts of interest to declare.
Acknowledgments

Setor K Kunutsor is funded by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and Leicester NIHR Biomedical Research Centre (BRC). The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care.

Author Contributions

Conceptualization, Data curation, Formal analysis, Investigation, Visualization: TGC, JYK, SYJ. Funding acquisition: SKK. Methodology: TGC, JYK. Supervision: SYJ. Writing–original draft: TGC, JYK. Writing–review & editing: TGC, SKK, SYJ.

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