Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a β-coronavirus, has caused millions of deaths worldwide by causing the coronavirus disease (COVID-19). Coronaviruses are enveloped, positive-sense single-stranded RNA viruses that can be divided into 4 genera: α, β, γ, and δ; with SARS-CoV-2 classified as a β coronavirus [1]. The four structural proteins of coronaviruses are spike (S), membrane (M), envelop (E), and nucleocapsid (N) [2] The spike binds to angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV. ACE2 expression is high in the lung, heart, ileum, kidney, and bladder, all of which can be implicated with the infection of SARS-CoV-2. Infection with SARS-CoV-2 can range from an asymptomatic acute infection with full recovery, to a life-threatening and fatal disease, requiring urgent medical treatment. One of the most dangerous aspects of COVID-19 is that it can result in a chronic, debilitating illness with persistent symptoms not just in the elderly or those with underlying co-morbidities, but also in young, healthy persons. A significant proportion of individuals experience symptoms following infection, which can be sub-categorised into acute post-COVID syndrome for symptoms persisting three weeks beyond initial infection and chronic post-COVID syndrome for symptoms persisting beyond twelve weeks {NICE Guidelines -[3]} (Fig. 1). Long-COVID is a term used to identify the presence of symptoms after acute COVID-19. SARS-CoV-2 can affect multiple organ systems in the body, including the cardiovascular, respiratory, musculoskeletal, immune, and metabolic systems, leading to acute organ damage and long-term sequalae [4] (Fig. 1). To date, common symptoms in individuals with long-COVID include profound fatigue, breathlessness, cough, chest pain, palpitations, headache, joint pain, myalgia, insomnia, diarrhea, rash or hair loss, neurocognitive issues including memory and concentration problems, often with one or more symptoms present [5] (Fig. 1). Exercise therapy has shown to be effective as an adjuvant therapy to treat multiple chronic diseases, and recent evidence has shown that this may also be the case for treating COVID-19 infections. More evidence and research from multi-disciplinary teams is crucial to understand the mechanisms, rehabilitation and implications of long COVID-19 andthe potential role of exercise therapy as an effective adjuvant treatment option. This review article summarizes the long-term symptoms of COVID-19 and the implications and outcomes of exercise interventions as a method of treatment.

Fig. 1
figure 1

Defining the timeline and symptoms associated with long COVID infection. A Time course of long COVID infection. B Major symptoms experienced in the acute phase of infection with COVID-19 lasting approximately 2–6 weeks post infection. C Persistent symptoms associated with Long COVID infections lasting for longer than 3 months

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Methods

Major databases including PUBMED, Embase, Web of Science and Scopus were searched for selecting relevant articles for discussion. Search terms for Coronavirus OR Sars Cov2 OR COVID-19 AND long-term effects/symptoms OR persistent effects/symptoms OR post-acute sequelae of COVID-19 (PASC) was used to find articles via MeSH terms or All Fields. The reference lists of identified articles also searched for further identification of relevant articles. Similarly, Exercise interventions were searched in combination with long COVID or with relevant physiologic symptoms to identify articles describing the exercise interventions that can mitigate the persistent symptoms of COVID [6]. The information obtained from the selected articles was collated and presented in a narrative review under four main headings: Section 1. Long-term symptoms of COVID; Section 2: Multi-system benefits of exercise; Section 3: Relationship between Long-term covid symptoms and Exercise; and Section 4: Current Exercise interventions in post-covid syndrome.

Section 1: Long-term symptoms of COVID

Long COVID is defined by WHO as a “post-COVID-19 condition” that occurs if symptoms persist three months after infection and for which there is no alternative diagnosis. Figure 1 below summarises the symptoms frequently reported to be associated with COVID-19 infection that tends to persist for longer than three months [7,8,9,10].

Respiratory symptoms

Respiratory sequalae have been described to be a prevalent long-term health effect of COVID-19. However, long-term consequences on the lungs have not been well reported, with most literature focused on case reports and case series. This review summarizes respiratory complications of long COVID-19 (post-acute sequelae of COVID-19, or PASC). The most common sites of infection of SARS-CoV-2 are the upper and lower respiratory tracts, with the severity of the damage corresponding to the severity of the infection [11,12,13]. Type 2 pneumocytes found in the lung are directly attacked and destroyed by SARS-CoV-2. The degree of damage to the lung depends on the release of pro-inflammatory cytokines resulting from the impaired type 2 pneumocytes in conjunction with the effects of viral replication [11, 12]. Infection can lead to various pulmonary complications like chronic cough, fibrotic lung disease, bronchiectasis, and pulmonary vascular disease [14]. A study by Fabbri et al. [15], indicated that the fibrotic changes in the lung post-viral infection can persist for years. SARS-CoV-2 can induce pulmonary fibrosis via the promotion of the upregulation of pro-fibrotic signaling molecules [16]. Following SARS-CoV-2 infection, the development of pulmonary fibrosis can progress via the formation of intra-alveolar thrombosis and airway inflammatory damage [16]. Lung abnormalities can be identified through CT scans post-SARS-CoV-2 infection. A study followed a cohort of individuals post infection for 4 – 6 weeks and found that upon CT imaging 32% had interstitial lung changes [17]. Analyzing post-COVID-19 implications of a severe infection, a study illustrated that 44% of patients had an abnormal chest X-ray (CXR) at six months [18]. Another study showed that 35% of individuals had fibrotic-like changes six months post-recovery from severe COVID-19 pneumonia, with 38% having complete radiological resolution [19]. Evaluation of lung health post-infection is necessary for understanding the intensity and severity of long-COVID and its health implications. There have been reports of several respiratory complications secondary to COVID-19 contributing to the effects and enhancing the symptoms of long-COVID. Bronchiectasis has been reported after infection, and the indications for the disease can be either due to the disease itself or due to a bacterial infection [20]. A study conducted in China on 81 patients found that 11% of individuals had evidence of bronchiectasis post-COVID-19 [21]. Studies looking at the predictors of post-COVID lung disease illustrated that there was a correlation between the extent of abnormality on HRCT 5 months after discharge and the severity of illness [22]. Therapies targeted for patients with post-COVID lung disease are still being investigated, with no therapy currently approved for post-COVID lung fibrosis.

Cardiovascular symptoms

COVID-19 poses many long-term implications for cardiovascular health, which will be explored in this section. Through its mechanistic binding to ACE2 receptors via the spike (S) protein, SARS-CoV-2 has been shown to induce myocardial damage, as the cardiovascular system expresses the ACE2 receptor rendering it vulnerable to infection. SARS-CoV-2 can indirectly or directly infect cardiomyocytes. Previous studies suggested that the mechanism of cardiovascular complications such as fulminant myocarditis was a result of a hyperinflammatory state and a cytokine storm [23]. It is supported by a study that myocardial injury associated with COVID-19 can be a result of direct infection of cardiomyocytes and the cardiotoxic effect of the SARS-CoV-2 infection, and not from hypoxia and inflammation [24]. Cardiac troponin levels that have been found to be frequently elevated in COVID-19 patients, indicating an associated level of myocardial injury with the onset of infection [25, 26]. It was found that myocardial injury occurred in 7.2–40.9% of patients with COVID-19, with the indications of myocardial biomarker levels unrelated to coronary artery disease being analyzed [27, 28]. A retrospective cohort study based in the UK showed that the diagnosis of COVID-19 was linked to a three-fold increased risk of major adverse cardiovascular events up to 4 months from diagnosis [29].

There has been a rise in reported incidences and analysis’ through studies of cardiovascular issues pertaining to SARS-CoV-2 infection. Davis et al., [30] conducted an international online survey study undertaken of 3762 patients, symptoms related to cardiotoxicity including chest pain (∼53%), palpitations (∼68%), fainting (∼13%) were observed in up to ∼86% of patients for up to 7 months following infection. A study using the US Department of Veterans Affairs National Health Care database found that beyond the first 30 days of infection, individuals infected with SARS-CoV-2 illustrated increased risks and 12 month burdens of cardiovascular diseases; including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease, and other cardiac disorders [31]. The results found were also apparent in individuals with no prior history of cardiovascular disease before exposure to SARS-CoV-2. The study’s results were important as they highlighted the incidence rates of cardiovascular comorbidities in individuals who were non-hospitalized vs hospitalized vs those admitted to intensive care [31]. It has been reported that dysautonomia, a condition caused by the malfunction of the autonomic system, is a manifestation of the chronic sequelae of long-COVID infection [23]. Additionally, a study showed that sinus arrhythmia is frequently presented in long-COVID, and manifests as transient or sustained periods of sinus tachycardia or bradycardia [32]. Possible predictors of underlying cardiac manifestations with long-COVID still require more research; however, an analysis of the literature indicates that infection with SARS-CoV-2 can have cardiovascular implications post-infection.

Musculoskeletal symptoms

Musculoskeletal symptom presentation amongst long haulers has been quite frequently reported, however, there has been a lack of overview in the literature on the impact of PASC on the musculoskeletal system. A study comparing patients who experience musculoskeletal symptoms post-infection versus those who did not experience symptoms found that most of the patients had fatigue (71.8%), spine pain (70.7%), and myalgia (60.7%), with the most common pain region being the back (30.4%) [33]. Musculoskeletal symptoms can limit an individual’s capacity and can contribute to a decrease in quality of life. The onset of musculoskeletal symptoms must be understood and reviewed to allow for rehabilitation programs to be established for individuals facing the effects of long-COVID. A study of 367 individuals that included hospitalized and non-hospitalized patients found that 55% of patients experienced fatigues in the 6 months after COVID-19 diagnosis, and 38% experienced myalgia [34]. Additionally, in a prospective study of 300 patients, Karaarslan et al. [35, 36] found that about three-quarters of the participants had one or more musculoskeletal symptoms after the first month of infection. The highest reported musculoskeletal symptom reported was fatigue (44.3%), followed by back pain (22.7%), arthralgia (22.0%), myalgia (21.0%), low back pain (16.3%), and neck pain (10.3%). Moreover, a study conducted via a web-based survey with a sample of 616 individuals in Italy found that clinical features of fibromyalgia are common in long-COVID musculoskeletal symptoms, with obesity and male gender having an effect on the risk of developing post-COVID-19 fibromyalgia [37]. Although the pathophysiology, mechanism, and persistence of musculoskeletal symptoms post SARS-CoV-2 infection is largely unknown, the systemic immune response with inflammation, direct viral toxicity, hypercoagulability and microvascular injury is currently proposed as one of the few suggested mechanisms [38]. Additionally, the role of cytokines and the cytokine storm is proposed as a suggested key mechanism in the development of musculoskeletal symptoms post-SARS-CoV-2 infection [39]. CXC motif chemokine ligand 10 (CXCL10), interleukin (IL)-17 and tumor necrosis factor alpha (TNF-α) may have a role in the decreased formation and deconstruction of bone and joints respectively [40]. IL-1β, IL-6 and TNF-α are cytokines responsible for causing chondrolysis, resulting in arthralgia, which has been seen as a musculoskeletal symptom post-infection. Additionally, IL-1β, IL-17 and TNF-α are thought to promote inflammation and cause possible exacerbation of degenerative tendon disorders [40]. Future studies should investigate musculoskeletal symptoms in combination with laboratory findings of inflammatory and infection related parameters. Musculoskeletal symptoms during long-COVID-19 infection are increasing in prevalence, and the underlying mechanism along with rehabilitation strategies should be further explored to help with the onset of the symptoms.

Central nervous system effects

The central nervous system is one of multiple organ systems affected by the SARS-CoV-2 virus. Neurological complications associated with COVID-19 can range from mild symptoms such as a headache to more severe symptoms such as psychosis, anosmia, and stroke [41, 42]. A study also showed that adults have a double increased risk of developing a psychiatric disorder after COVID-19, which can influence the symptom presentation in long-haulers [43]. In a prospective study of 100 non-hospitalized COVID-19 “long haulers” it was found that the main neurologic manifestations were brain fog (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%) [44]. Additionally, another study indicated that 65% of the patients reported neurological symptoms of fatigue (80%) post-exertional malaise (73%) and cognitive dysfunction (58%) beyond 6 months of infection. A recent meta-analysis including data from 47,910 patients found that patients infected with SARS-CoV-2 developed one or more long-lasting neurological symptoms, with the most frequent being fatigue (58%), headache (44%), attention disorder (27%), and anosmia (21%) [45, 46]. Brain fog is another neurological symptom that has shown to persist as long as 5 months, with patients presenting with brain fog displaying short-term memory and attention deficits [44]. It is evident that infection with COVID-19 manifests neurological symptoms that not only ranges in its severity but can have long-lasting implications on the central nervous system. Although the pathophysiology of SARS-CoV-2 invasion in the central nervous system is not fully understood, there are proposed mechanisms of neuro-invasion which consist of direct and indirect effects of involvement on the central nervous system. Direct involvement of SARS-CoV-2 cerebral invasion is proposed to be through dissemination across the cribriform plate of the ethmoid bone [47]. Another direct proposed mechanism of SARS-CoV-2 cerebral invasion is through the ACE2 receptor. The ACE2 receptor has been detected over glial cells and neurons which makes the central nervous system a potential target for COVID-19 [48, 49]. Additionally, binding to ACE2 can increase the risk of cerebral hemorrhage and ischemic stroke due to elevated blood pressure [47]. Studies have illustrated that hemorrhagic stroke is less prevalent than ischemic stroke in its association with COVID-19 [50]. The role of the immune system and the cytokine storm also serves as a proposed mechanism for the neurological symptoms presented with long-term COVID-19. The increase in the release of pro-inflammatory cytokines, interferons (IFN), interleukins (IL), and tumor necrosis factor-alpha (TNF-α), can result in blood barrier disruption [51]. Studies have reported a sign of cytokine storm syndrome in a group of COVID-19 patients through brain CT scans and MRI Reports [52]. The cerebral invasion of SARS-CoV-2 through synergistic mechanisms has shown to have long lasting central nervous system effects. Future studies should investigate neuroprotective therapies, and immunomodulators to help combat the long-lasting central nervous symptoms experienced with long-COVID-19.

Section 2: Multi-system benefits of exercise

There is overwhelming evidence that there are several benefits to participating in regular and consistent exercise. These benefits include but are not limited to; decreasing mortality and morbidity, reducing disease risk factors and disease progression, and helping to improve the overall quality of life [53] (Fig. 2). Furthermore, the benefits of physical activity can influence several organ systems because of the physiologic responses that exercise has on the body (Fig. 2) [54]. For instance, there is evidence that a sedentary lifestyle is associated with the development of various conditions such as hypertension, obesity, atherosclerosis, diabetes, congestive heart failure, some types of cancer, impaired immunity and cognitive dysfunction [54,55,56]. It’s possible to see the vast benefits of exercise by evaluating its effects on individual systems that are greatly impacted by physical inactivity. Research has shown that exercise induces adaptations in several different cell types and tissues throughout the body and challenges whole-body homeostasis, thus providing systematic health benefits [54, 57, 58]. These types of findings have important implications from both a public health and a clinical perspective, as it demonstrates that regular exercise can potentially be included as part of treatment for a variety of diseases in addition to traditional treatment measures such as prescription medications and surgeries.

Fig. 2
figure 2

Physiologic responses and health benefits of Exercise

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The effect of exercise on cardiovascular function

The first system that comes to mind when discussing the benefits of exercise on chronic diseases is the cardiovascular (CV) system. The Global Burden of Cardiovascular Diseases study by Roth et al. [59, 60], demonstrated that CVD is still the leading cause of disease worldwide, based on global trends from 1990 to 2019. CVDs of particular interest include ischemic heart disease, stroke, and hypertensive heart disease, all of which exhibited steadily increasing rates of incidence since 1990 [60]. There are several potential drivers of CVD including cardiometabolic, environmental, social and behavioural risk factors, thus making it more difficult to identify and target a specific cause for a particular CVD [59, 60]. Of particular interest for these drivers are modifiable risk factors, which have shown an increasing trend on a global scale. Given these alarming statistics, it is essential that research focuses on identifying cost-effective therapeutic interventions to effectively combat these modifiable risk factors and the overall increasing incidence of CVD worldwide.

The protective effects of regular physical activity on CV health are widely accepted. It is well known that a sedentary lifestyle is a major risk factor for cardiovascular diseases (CVD), in addition to other important CVD risk factors such as high blood pressure, obesity, smoking and abnormal blood lipid values [61]. Several studies have demonstrated that exercise can positively impact traditional and non-traditional CVD risk factors such as reducing blood pressure and body weight, increasing insulin sensitivity and increasing exercise tolerance [61]. Therefore, regular exercise is associated with a decrease in CV mortality, a decreased risk of developing CVD as well as contributing to improving cardiac performance [61, 62]. Different exercise prescriptions, i.e., different modalities, intensities, and duration, have various effects on health but overall, the evidence is overwhelming that physical activity is a major mitigator for CVD. In fact, moderate to vigorous exercise is not only a preventative factor, but also now widely prescribed by physicians for the treatment of various CVDs such as myocardial infarction, angioplasty and congenital heart disease [62,63,64]. Therefore, as exercise has shown to an effective tool for both delaying the onset and progression of CVD, it can be used as a critical therapeutic tool to improve outcomes in patients suffering from CVD.

One of the most important measures of health is cardiorespiratory fitness (CRF), as this measure is inversely associated with disease severity. Low CRF is associated with higher CVD morbidity and mortality [65, 66]. CRF is commonly measured by maximal oxygen uptake (also known as VO2 max), as this reflects the body’s ability to utilize oxygen during exercise. This is vital because the human body is physiologically very sensitive to a reduction in physical activity. For instance, as little as two weeks of reduced exercise can lead to a decrease in CRF [67]. It is well established that physical activity is an important modulator of CRF and so it is proposed that by increasing daily physical activity intake, this will lead to an improvement in CRF and contribute to mitigating CVD risk factors, and thus decreasing disease incidence and severity [66, 68].

As briefly discussed above, there are several proposed mechanisms as to why regular physical exercise has several beneficial effects on CV health. Such mechanisms include increasing aerobic respiration or CRF in cardiomyocytes and skeletal muscle myocytes, more efficient tissue oxygen delivery via increased vasodilation and angiogenesis, as well as have anti-inflammatory effects [61, 64, 69]. These mechanistic processes appear to improve CV health because CVD is considered a multi-factorial disease, as opposed to having just one causative agent. Therefore, the beneficial effects of exercise are not exclusive to the CV system, and this will be discussed in the subsequent sections looking at the effect of exercise on other organ systems.

The effect of exercise on respiratory function

The burden of lung diseases worldwide is high, such that respiratory diseases are among the leading causes of death worldwide [70,71,72,73,74]. Most notably are lung infections like pneumonia and tuberculosis, chronic obstructive pulmonary disease (COPD) and lung cancer [72, 74]. In addition, the impact of lung disease incidence and prevalence on society not only includes its mortality rate but also includes the extent of disability caused by lung diseases. It is well known that poor lung function is associated with all-cause mortality from chronic lung disease, and a strong risk factor for CVD and lung cancer [75, 76]. Of particular interest is forced expiratory volume (FEV), as this has shown to be an important measure of lung function, and thus a potential predictor and risk factor of morbidity and mortality [76]. Newer evidence demonstrates that there is a relationship between regular physical activity and mortality from lung diseases, but the evidence is less robust than the research conducted to investigate the relationship between exercise and CVD, as reported in Sect. “The effect of exercise on cardiovascular function”. However as limited as the research is, there still appears to be an important link between regular exercise and increased lung function (FEV).

For instance, one longitudinal study conducted by Pelkonen et al. [77]demonstrated that a high level of physical activity was associated with a slower decrease in pulmonary function (measured with an FEV test) and lower mortality, in a cohort of middle-aged males [77]. The authors sought to evaluate whether the effects of exercise (walking, cycling and skiing) were successful in slowing the natural decline in pulmonary function with increasing age, in male participants aged 40–59. After adjusting potential confounding factors like diastolic blood pressure, total cholesterol, smoking and age, the results during the 25 year follow-up period demonstrated that physical activity helped delay the decline in pulmonary function, that normally occurs in middle and old age [77]. Furthermore, Jakes et al. [76] performed subsequent analyses from the large European Prospective Investigation in Cancer (EPIC) Norfolk study, to also investigate this important relationship. The cross-sectional results provided further evidence that there is a longitudinal relationship between physical activity and the rate of change in FEV, such that participants with a higher level of vigorous activity demonstrated a slower rate of FEV decline, compared to their less active counterparts [76]. Several other studies have also found similar results that demonstrate that exercise has potential benefits for the respiratory system and pulmonary function [78,79,80].

The effect of exercise on musculoskeletal system

The musculoskeletal system (MSK) is responsible for movement and is therefore the organ system that appears to be positively affected by physical activity. The majority of evidence from studies linking the benefits of exercise on the MSK are in clinical populations, such as in patients with osteoarthritis (OA), fibromyalgia, muscular dystrophies and sarcopenia [81,82,83,84]. Given the nature of these MSK diseases, the goal of exercise therapy is to help reduce pain and disability, by increasing or maintaining mobility in the bones and muscles.

In the past, it was controversial and potentially harmful to prescribe physical activity like aerobic exercise or resistance training as a treatment for MSK diseases. Of course, individualized medicine is still important to effectively treat a patient’s symptoms and condition, but clinicians have generally debated whether or not muscle exercise is beneficial or harmful for myopathic disorders [83]. However, more recent evidence has emerged suggesting benefits. One study conducted by Van Baar and co-authors [84] performed a systematic review of trials to evaluate the effectiveness of exercise interventions vs. a placebo/no treatment, in patients suffering from mild to moderate OA. The results of this literature search demonstrated that there is evidence that there are various beneficial effects of exercise interventions in OA patients. Specifically, the participants randomly allocated to the exercise intervention group exhibited improvements in a variety of measures including decreased pain reporting, improved walking performance and increased level of mobility [84]. However, given the small number of studies and small sample sizes of some of the studies in the systematic review, there was little to no evidence available to determine which exercise program (i.e. duration, intensity or modality) was the most effective in improving the measured health outcomes [84]. More research is required to investigate this, as this has clinical implications for exercise prescriptions for patients suffering from different MSK conditions.

Further research and a better understanding of the underlying molecular causes and mechanisms of muscle diseases have contributed to the shift in favour of exercise as a safe and effective therapeutic tool for MSK disease treatment [81,82,83,84]. Proposed causative mechanisms of MSK diseases include a variety of cellular pathways that can independently or dependently result in exercise intolerance, leading to further symptom exacerbation, thus causing a progressive cycle of poor health outcomes. Possible causes of different MSK conditions range from genetic to acquired factors, which may or may not be interactive with each other [83]. Therefore, the cause of MSK diseases usually cannot be narrowed down to a single causative agent, similar to CVDs. However, the loss of skeletal muscle mass has been shown to be one of the main pathogenic factors of reduced muscle force generation, leading to increased fatigue and thus a major contributor to exercise intolerance [83]. For instance, one pathway implicated in the exercise fatigue theory of MSK diseases is oxidative stress [85]. It is believed that an increased production of reactive oxygen species (ROS) in muscles causes cellular and tissue damage, contributing to decreased muscle contraction and thus an increase in the level of fatigue [82, 83, 85]. This is important from a clinical perspective because abnormal oxidative stress levels are considered a core causative agent of not just MSK conditions, but also metabolic and immune system diseases, which will be discussed in the next section in further detail. It is well established that exercise can have potent systemic antioxidant effects, meaning that it can help prevent and alleviate the harmful cellular and tissues damage caused by ROS [70, 71, 86]. This antioxidant effect may help explain why exercise can result in less fatigue and symptom improvement in patients suffering from MSK diseases. Therefore, this provides further evidence and support for the use of exercise in the treatment plan for various MSK conditions, in addition to other traditional treatments forms.

The effect of exercise on metabolic and immune system

There is growing evidence that immune cells, including cytokines and other innate and adaptive immune cells, play a role in the development of various conditions affected by physical inactivity such as hypertension and type 2 diabetes mellitus (T2DM) [87,88,89,90], as well as the incidence of communicable diseases such as viral infections [91]. As briefly discussed above, oxidative stress and systemic inflammation (two important processes involved in the underlying mechanisms of several metabolic and inflammatory diseases) appear to be mitigated by moderate exercise [89, 91]. Furthermore, there appears to be several links between the immune and endocrine system [89], which may explain why regular physical activity has beneficial effects on different diseases involving a mix of imbalanced hormones and low-grade, systemic inflammation mechanisms, such as T2DM. Pederson et al. [89] reviewed various studies to evaluate the current evidence for exercise-induced changes in neuroimmune interactions, specifically looking at the effect of exercise on circulating levels of catecholamines (e.g. epinephrine), cortisol, growth hormone, endorphins and sex steroids. Given the important role of these hormones in different pathological metabolic states, it is evident that there is a relationship between the immune and metabolic system, whereby diseases involving these systems, can be mitigated by exercise [89].

It is proposed that exercise can help boost the immune system by releasing anti-inflammatory cells during and after exercise, cause an increase in cell recruitment and lymphocyte circulation, all of which are essential for host defense [64, 87, 89, 91,92,93]. Of particular interest is the decrease in low-grade systemic inflammation with exercise, mediated via anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-beta, and an increase in lymphocyte concentration like neutrophils, which helps prevent infections by intra-cellular microorganisms [89, 91]. Altogether, this antioxidant response from regular physical activity has been shown to help decrease the severity of symptoms, intensity and mortality from viral infections, including COVID-19 [89, 91, 93, 94]. The impact of exercise on COVID-19 specifically will be discussed in further detail in Sect. “Relationship between Long-term covid symptoms and exercise”.

However, there is some controversial evidence regarding the effects of different exercise intensities on cellular immunity to infections [88, 89, 91]. For instance, it is proposed that moderate-intensity exercise is the most beneficial intensity of exercise for stimulating cellular immunity against infections, whereas excessive or high-intensity exercises with minimal rest periods, can actually induce decreased cellular immunity, making a patient more susceptible to infections [89, 91]. Therefore, while it appears that regular exercise, as opposed to a sedentary lifestyle, has benefits for decreasing the incidence and severity of various chronic diseases involving the immune system, it is still important to take an individualized medicine approach to treatment, as each patient is a unique case.

The effect of exercise on mental health

Given the increasing global prevalence and burden of mental health conditions such as depression and anxiety, there is a rise in research focusing on mental health outcomes and the need to find simple, effective treatments to treat these conditions [95]. Of particular interest is exercise. Research has shown that exercise can have beneficial, physiological effects on mental health including an improvement in mood and self-esteem, a decrease in stress levels and alleviation of mental health symptoms, which all contributes to an improvement in psychological well-being [96, 97].

To date, there is no conclusive evidence to argue that there is one specific mechanistic pathway to explain how exercise influences mental health, as there is a wide spectrum of conditions and symptoms, and several benefits of exercise. However, there are various proposed biological mechanisms underlying this relationship between mental health and exercise, including reduced inflammation, the role of endorphins, altered neurotransmitter levels, and an attenuation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress [96, 98]. As described in detail in the above sub-sections, exercise has the ability to reduce systemic inflammation. The positive anti-inflammatory effects of exercise also extends to mental health, as inflammation has shown to play a role in the pathogenesis of common mental health conditions such as anxiety and depression [96]. In addition, there are various hypotheses that have been proposed to help explain the benefits of exercise on psychological well-being, such as the mastery and self-efficacy hypothesis [96, 98]. These hypotheses highlight the relationship between exercise, confidence, self-esteem and mood. It proposes that individuals who are able to self-regulate their daily routine and successfully reach a set goal such as completing an exercise session, are less susceptible to depressive behaviour and have an increased ability to tackle events that may challenge their mental health [96, 98]. Overall, these hypotheses provide evidence that a higher level of perceived self-efficacy and control over one’s actions contribute to the exhibited elevation in mood and improvement in mental health associated with regular exercise [96, 98].

A cross-sectional study conducted by Khanzada et al. [99] demonstrated an important association between physical inactivity and levels of anxiety and depression in a population of adults aged 18 to 45 years. The authors found that in the non-exercising participants, there was a significantly higher level of reported anxiety and depression compared to their exercising counterparts, indicating that regular physical exercise was significantly associated with lower anxiety and depression frequency [99]. Similarly, a recent systematic review of 40 studies conducted by Herring et al. [100] demonstrated that exercise training had a significant overall mean effect for decreasing anxiety symptoms, among patients with a chronic illness. Currently, physical activity is only recommended as an adjunctive self-treatment for mental health, based on a consensus by the National Guideline Clearinghouse [101, 102]. However, there has been an increase in recent robust evidence from several comprehensive reviews and meta-analyses [96,97,98, 100, 102], demonstrating the positive effects of exercise on various aspects of mental health. Therefore, it can be argued that there is an increase in support for the use of exercise as an adjuvant approach to mental health treatment, in addition to traditional treatment options like medications and psychotherapy.

Section 3: Relationship between LONG-term COVID symptoms and Exercise

Exercise has been shown to be effective in improving long-term health outcomes across various systems, as discussed in section two. Figure 3 summarises the potential benefits of exercise therapy that can be used to target symptoms associated with long-term COVID. The studies discussed in this section clearly demonstrate the effect of exercise in reducing similar symptoms experienced due to various types of illness, leading to improvement in both physical and psychological quality of life (QoL).

Fig. 3
figure 3

Exercise interventions for mitigating long-term COVID symptoms

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A meta-analysis conducted on articles examining the efficacy of exercise as an intervention in clinical populations, relative to its effect in well populations, found that an increase in both physical and psychological quality of life (QoL) was observed in well populations and rehabilitation groups [103]. Interestingly, when treatment goals were examined for prevention/promotion (well populations), rehabilitation, or disease management, significant disparities in outcome were discovered. The total QoL of rehabilitation patients showed a moderately beneficial effect of exercise interventions three to six months from the baseline, although well-being or disease management groups did not show any meaningful effects. However, compared to controls, well participants’ physical and psychological QoL dimensions considerably improved [103]. The authors concluded that this was due to the purpose of the intervention in maintaining a level of function [103], and this indicates that exercise could have positive effects on patients experiencing long-term COVID symptoms, as here the intervention would be aiming to alleviate those symptoms and hence restore physical function.

Furthermore, exercise intervention at various intensities was demonstrated to improve physical QoL across all patients examined—this finding is promising for the implementation of exercise programmes in the treatment of long-term COVID symptoms. Many of the symptoms of PASC are present in other pathological conditions where exercise has proven a useful tool for symptom management (Fig. 3), indicating its potential as an intervention, which will be examined further in this section [87, 93].

Efficacy of exercise in the treatment of lung fibrosis

One of the most prevalent respiratory sequelae in PASC is fibrotic lung disease [104]. Exercise therapies have been shown to be effective in mitigating the effects of lung fibrosis in bleomycin-induced mouse models, one of the leading models for lung fibrosis [105].

Aerobic exercise training was found to improve physical capacity in test groups with and without the bleomycin treatment to a similar extent, while the control group and the fibrosis group which received no training showed no such improvement [105]. Additionally, the presence of collagen fibers (expressed as a % of the total lung tissue) was higher in the fibrosis-only group compared to each of the other groups, indicating that exercise training played a role in slowing the development of fibrosis [105]. The mechanism by which exercise improves physical capacity is thought to be the inhibition of serotonin (5-hydroxytryptamine/5-HT) and protein kinase B (PKB) signaling; these signaling pathways promote fibroblast growth, reproduction and survival [106] and levels of 5-HT are elevated in lung fibrosis. Aerobic exercise training has been shown to have an inhibitory effect on 5-HT synthesis, tending to restore it to normal levels [107] and in the bleomycin mice models, levels of both 5-HT and phosphorylated PKB were reduced in the exercise-trained fibrosis group compared to the fibrosis only group [105].

In one case report following a COVID patient experiencing lung fibrosis sequelae (as diagnosed from patient presentation and CT scan) who was unable to cut off oxygen supplementation even following a recovery from COVID-19 infection; pulmonary rehabilitation in the form of structured exercise-based intervention was successful in allowing the patient to exit from the hospital without any activity limitations [108]. At the start point of rehabilitation, the patient was otherwise physically well but due to the fibrotic damage sustained from COVID infection was unable to walk more than 200 m independently while supplemented with oxygen. The rehabilitation programme consisted of 10 supervised physical therapy sessions, at a 5 day per week frequency, 12–14 on Borg Rate of Perceived Exertion (RPE), 60 min per day of stretching, strengthening and aerobic exercises [108]. The intensity was managed every 10 min to maintain it. After 8 days of this routine, the patient showed considerable improvement in lung function and was able to complete the exercises without requiring oxygen supplementation [108]. Based on CT scans, the programme successfully expedited the patient’s recovery; however, lung fibrosis was persistent, although it showed a significant reduction during a follow-up 3 months later [108]. While exercise cannot reverse fibrosis, this case shows the potential for it as a rehabilitation treatment for long-term complaints of lung fibrosis in COVID patients.

Efficacy of exercise in the treatment of cardiovascular comorbidities

One of the most common cardiovascular comorbidities arising following recovery from a COVID-19 infection is myocarditis, often directly resulting from the cardiotoxic effects of the infection [109]. One complication arising in myocarditis which can result in aggravation of the damage to the myocardium occurs due to subacute immune response, in which T cells and B cells can increase the size of the damage through cytokine activation and production of antibodies against viral proteins [110]. Regular exercise can influence the activity of the immune system—those who practice regular moderate-intensity exercise can experience heightened vaccine response, increased T cell production, reduced inflammation in responses and an overall decreased chance of sickness [111]. However, once a diagnosis of myocarditis has been confirmed, exercise restriction is mandatory for the duration of the inflammation, and athletes were recommended to return to competitive sport only after ventricular systolic function normalized, serum markers of inflammation (troponin, brain natriuretic peptide, C-reactive protein, erythrocyte sedimentation rate) returned in the normal ranges, and arrythmias were absent [111].

In terms of other cardiovascular complications arising from long-term COVID symptoms, exercise has several health benefits (Fig. 3), which makes it ideal for use in a rehabilitation/support programme, due to the release of myokines associated with physical exercise [112]. These myokines have various positive effects, including: protecting against muscle atrophy, preventing the excessive production of adipose tissue, improving vascular injury, endothelial function and myocardial ischemic damage. They also play a role in the development of arterial hypertension and may have anti-diabetic and anti-CKD (Chronic Kidney Disease) effects [112]. All of the above factors provide evidence that exercise may help prevent the development of risk factors for cardiovascular disease in patients suffering from these symptoms.

Efficacy of exercise in treatment of musculoskeletal symptoms

Three common musculoskeletal complaints from patients suffering from long-term COVID symptoms include myalgia, fatigue and chronic back/spine pains [34, 39, 40]. In one randomized controlled trial evaluating the benefits of graded exercise therapies in patients diagnosed with chronic fatigue syndrome, excluding patients with psychiatric disorders or insomnia, the findings encouraged the use of this treatment [113]. Exercise was tested against flexibility and relaxation therapies administered by exercise physiologists, while the exercise therapies themselves were graded based on each patient’s physical capacity. Patients were assessed for improvements in their QoL primarily and their fitness and symptoms secondarily, at 12 weeks, 3 months and 1 year after cessation of supervised treatment. Of the exercise group, 16 out of 29 participants rated themselves as significantly improved, whereas only 8 out of 30 participants reported the same from the flexibility control group [113]. Additionally, patients from the exercise group showed greater improvements in physical health parameters than patients from the flexibility group, and similar benefits from the exercise treatments were seen at each follow-up interval (68% of patients who attended follow-up at 3 months reported significant improvements in QoL, and 74% reported significant improvements after 1 year) [113].

Exercise programme have also proven effective in treating chronic back pain. A systematic review of the literature surrounding exercise interventions in cases of chronic back pain found that exercise had no negative effects on patients despite their existing chronic pains, and in fact had either a neutral or slight positive effect on these patients [114]. When the programme is further tailored to target specific functions lost due to chronic back pain, greater benefits can be seen. Static stretching regimens targeted at restoring range of movement showed both high adherence rates and average improvements of roughly 20% in flexibility [114]. Resistance training at a frequency of at least once per week to improve lumbar extension strength showed improvements between 30 and 80%. Volume-adjusted exercise plan not contingent upon pain-oriented performance goals utilized to reduce fear-based avoidance contributing to continuing disability and poorer outcomes was successful in significantly boosting activity and exercise tolerance while simultaneously decreasing pain medication usage and intensive exercise programme aimed at reducing chronic pain symptoms enjoyed greater success than more moderate programme (36% vs 20%) [114]. However, it should be noted that some of the literature contests the efficacy of exercise as an intervention [114]. Aerobic exercise training also showed great short-term positive effects in the treatment of fibromyalgia when compared to stress management or the baseline treatments [115]. However, this effect was not present at follow-up, and in the case of exercise training poor adherence to the treatment over the long term was cited as an explanation for the homogenous symptom severity in the long term.

Efficacy of exercise in the treatment of neurological symptoms

The condition of brain fog has received new attention recently, due to the prevalence of it as a symptom experienced by COVID-19 survivors in the period following their immediate recovery from the virus [116]. In a meta-analysis conducted of patients hospitalized with COVID-19 infection, it was discovered that approximately one-third of the patients suffered from persistent fatigue and over a fifth of the individuals experienced cognitive impairment twelve or more weeks after their COVID diagnosis. Furthermore, an association was drawn between post-COVID syndrome and notable levels of functional impairment in these patients [117]. Implementation of exercise can contribute to recovery from cognitive impairment in other contexts; a randomized controlled trail for adults experiencing cognitive frailty found that high-speed resistance training implemented over the course of 16 weeks yielded significant improvements in the cognition and executive function of the intervention group compared to the baseline control [118]. Notably, combination treatment was more effective than either aerobic training or resistance training individually.

Neurological fatigue is another prevalent PASC complaint [119], often accompanying muscular fatigue. Exercise has been shown to have considerable beneficial effects in combating neurological fatigue in other pathological conditions wherein it can arise; one study examining fatigue in multiple sclerosis (MS), a demyelinating disease, noted exercise as an important component for interventions in combating symptoms [120,121,122]. It is imperative that the intervention be personalized, so as to avoid detrimental overexertion, but nonetheless aerobic exercise intervention was found to significantly improve QoL. Headache, another common PASC symptom, could also be addressed by exercise therapy [123]. Exercise intervention was reviewed alongside manual therapy (each individually, and both together) and found to be a successful intervention, which could be recommended to treat primary headache.

Section 4: Current exercise interventions in post-COVID syndrome

The symptoms found across patients suffering from post-COVID syndrome are varied, spanning multiple systems, and there is currently a need for clinically appropriate interventions aimed at managing these symptoms. A review conducted into the possible treatments for pulmonary fibrosis sequelae post-COVID-infection suggested numerous possibilities for the treatment of post-COVID pulmonary fibrosis using drugs already approved for other purposes, from fibrinolytic agents when acute respiratory distress syndrome (ARDS) develops to gluco-corticosteroids aimed at inhibiting the rate of fibrotic change and stromal vascular fraction to prevent inflammation—but ultimately concluded that further research is necessary to determine the most effective path of treatment [124]. Another review suggested the potential for spironolactone (with animal trials for the drugs yielding positive results) and tissue plasminogen activator (tPA) in patients without contraindications such as suspected intracranial hemorrhage, subarachnoid hemorrhage or internal bleeding as treatments in high-risk patients, but once again advises further research to determine appropriateness and universality of use [13]. Exercise intervention has been shown to be successful in case studies in treating COVID-19 patients experiencing fibrosis through limitation of the inflammatory damage [108].

Exercise has been implicated as an appropriate intervention for cardiovascular complications arising from PASC, due to its effects in triggering the systemic antioxidant response and hence modulating the inflammatory response produced by the infection, in addition to providing protective effects against endothelial dysfunction [125]. A note of caution, however; utilizing exercise therapies for cardiovascular comorbidities is only appropriate where there is no existing myocarditis; in those cases, a minimum of six months rest is necessitated prior to beginning any form of exercise-based rehabilitation. Excessive exercise treatment will also prove counterproductive; athletes exercising at high intensities and for long periods induced pathological changes to both the heart and the cardiac vessels, and the tendency for arterial calcification has also been seen in those with greater training than those without [126]. Dose-response and modality (resistance, aerobic, endurance training) must be considered when prescribing treatment, to ensure the best treatment outcomes [125]. While improved clinical outcomes in PASC have yet to be demonstrated through exercise, it has proven helpful in alleviating the development of comorbidities—provided the previous points are accounted for.

Exercise intervention is also useful in the treatment of brain fog arising from PASC, as part of lifestyle changes that optimize health outcomes and hence aid in the management of chronic symptoms [127]. As part of a multi-disciplinary response, exercise treatment alongside other lifestyle considerations such as sleep and diet holds potential for post-COVID syndrome symptom management [128]. According to the Stanford Hall consensus statement for post-COVID rehabilitation, exercise therapy at low intensities is recommended for initial treatment in patients in receipt of oxygen therapy, with a gradual increase in intensity in line with improvements in vital signs and symptoms; exercise was also implicated as part of a multi-disciplinary approach to musculoskeletal symptoms, with the setting of the intervention tailored to individual patient’s needs [129]. However, in part due to the expeditious approach to research into COVID-19, in an attempt to tackle the disease, extensive research into the modalities and efficacy of exercise in addressing cardiovascular and neurological symptoms of PASC, in addition to respiratory symptoms has yet to be conducted. There are notable limitations to exercise intervention; in particular, it should be noted that intervention at high intensities can contribute to exacerbation of symptoms, and that in cases of myocarditis exercise is strictly prohibited for between 3 and 6 months, and when prescribing exercise such concerns must be accounted for. Nonetheless, there is sufficient evidence supporting the beneficial potential for exercise therapy that further research is implicated.

Conclusions

Long-term complications arising from Sars-CoV2 infection have many negative effects on the sufferers across several bodily systems. Some of these symptoms, such as pulmonary fibrosis or myalgia, have been shown to improve with an exercise intervention, provided the programme are personalized. The modality and intensity of the intervention should be personalized to each patient, accounting for co-morbidities, exercise tolerance, etc. to yield maximal effects. Exercise intervention can benefit patients suffering from PASC, but the effect of different modalities and intensities is unclear. Nonetheless, the benefits of exercise therapy are sufficient that further research is implicated.