Cardiorespiratory fitness as a vital sign of CVD risk in the COVID-19 era

Abstract

The severe health consequences of the corona virus disease 2019 (COVID-19) pandemic have been exacerbated by the prevalence of cardiovascular disease (CVD) risk factors, such as physical inactivity, obesity, hypertension, and diabetes. Further, policy decisions during the pandemic augmented unhealthy lifestyle behaviors and health inequalities, likely increasing the global disease burden. Cardiorespiratory fitness (CRF) is a well-established biomarker associated with CVD risk. Emerging data demonstrate that high CRF offers some protection against severe outcomes from COVID-19 infection, highlighting the importance of CRF for population health and the potential for limiting the severity of future pandemics. CRF is best assessed by cardiopulmonary exercise testing (CPET), which will be an important tool for understanding the prolonged pathophysiology of COVID-19, the emergence of long-COVID, and the lasting effects of COVID-19 on CVD risk. Utilization of CRF and CPET within clinical settings should become commonplace because of lessons learned from the COVID-19 pandemic.

Introduction

The cardioprotective effects associated with higher levels of cardiorespiratory fitness (CRF) are well-established. Over the past 30 years, research has demonstrated the vast benefits of high CRF in reducing the risk of the most prevalent noncommunicable diseases, including cardiovascular disease (CVD), diabetes, and several forms of cancer.¹ The evidence is so strong that the American Heart Association issued a scientific statement advocating for CRF to be considered a clinical vital sign in 2016; the evidence in support of vital sign status for CRF has continued to grow since this publication.² However, less understood is the relation between CRF and infectious diseases, such as coronavirus disease 2019 (COVID-19). Worse outcomes in individuals infected with COVID-19 are linked to unhealthy lifestyle and CVD risk factors (i.e., physical inactivity, obesity, diabetes, hypertension).³ Considering the link between these factors and CRF, it is possible that an individual's CRF level may impact their response to an infectious disease. Indeed, mounting evidence demonstrates an association between low CRF and more severe outcomes during and following COVID-19 infection.4, 5, 6, 7 This paper will overview these findings, discuss how policies during the pandemic may have altered behaviors leading to a reduction in CRF, and highlight the importance of cardiopulmonary exercise testing (CPET) in understanding the sequalae of long-COVID.

Importance of CRF for COVID-19 prevention, disease severity, and recovery

CRF is an integrative measure of the body's physiological ability to take in oxygen from the environment, transport that oxygen to the working tissues, and utilize the oxygen to support strenuous activity. An individual's CRF level is primarily determined by exercise training history, genetics, and body weight.² CRF has been discussed widely in the literature as a protective mechanism against severe COVID-19 outcomes, with higher levels of CRF associated with reduced risk of hospitalization, the need for invasive treatments (i.e., mechanical ventilation) and mortality⁶ (Fig. 1 ). Brawner et al. (2021), were the first to investigate the relationship between CRF, measured before infection, with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hospitalization with COVID-19.⁴ They identified 246 patients who undertook a maximal exercise test to determine CRF (measured as peak metabolic equivalents [METs]) and subsequently tested positive for SARS-CoV-2. Within their sample, 36% were hospitalized and peak METs were lower in those that were hospitalized (6.7 ± 2.8 METs) compared to those who were not (8.0 ± 2.4 METs). While the authors recognize the need for a larger cohort analysis and subsequent investigation to determine the full extent of improved CRF and the reduced risk of post-viral complications, the data demonstrate that CRF is independently and inversely associated with the increased incidence of hospitalization due to COVID-19. Similarly, Ekblom-Bak et al. screened >400,000 participants and identified 857 patients (70% men, mean age 49.9 years) with severe COVID-19 outcomes, including hospitalization, intensive care, or death.⁶ Characteristics associated with severe COVID-19 outcomes were lower CRF, higher body mass index (BMI), and increased reporting of comorbidities. Interestingly, obesity and blood pressure-related risks were reduced when adjusted for CRF and other lifestyle variables. The authors concluded that lifestyle and socioeconomic factors are directly associated with the risk of developing severe COVID-19 outcomes and add further evidence to the importance of increasing CRF, which attenuates risk associated with important health factors (e.g., obesity and high blood pressure) and various socioeconomic factors (e.g., education level, marriage status, birthplace, occupation, income).

Fig. 1.

Summary figure indicating the impact of CRF on risk of COVID-19 infection and severity of outcomes after infection.

Christensen et al., also investigated whether CRF was associated with testing positive for COVID-19 and subsequent mortality.⁵ Adopting a prospective cohort study, the authors identified 2690 participants from the United Kingdom that had been tested for COVID-19 and had undertaken a CRF assessment, estimated via submaximal cycle test and using linear regression to estimate workload at the predicted maximum heart rate. Three hundred and forty-six participants tested positive for COVID-19 (13%) with high levels of mortality (n = 59, 17%). The likelihood of testing positive for COVID-19 was not associated with estimated CRF (Fig. 1) but those with low CRF (<20th percentile) had more than double the risk of dying from COVID-19 compared to those with moderate or high CRF.⁵ Furthermore, Af Geijerstam et al., screened >1.5 million men that undertook military conscription in early life to compare the incidence of severe COVID-19 outcomes in later life via a prospective registry-based cohort study in Sweden.⁸ When compared with lower levels of CRF (measured from an exhaustive cycle exercise test), those with higher CRF during early adulthood had a reduced likelihood of developing severe COVID-19 outcomes in later life, reducing hospitalization (n = 2006), admission to intensive care (n = 445), and mortality (n = 149). While these data offer insight and support for the importance of CRF, it is unclear if maintaining high CRF in later life or if the change in CRF over time was associated with severe COVID-19 outcomes. Collectively, this emphasizes the importance of interventions to maintain or increase CRF in the general population to strengthen the resilience to severe COVID-19 and chronic health conditions. Although the mechanisms of protection are outside of the scope of this article, they have been discussed elsewhere.³ Furthermore, evidence of additional protection from increased levels of CRF is prominent,4, 5, 6, 7, 8, 9, 10 yet there is also a real need to determine the role that CRF plays in the prevention and development of long-term sequelae following COVID-19, which impacts CRF, exercise tolerance, and more broadly quality of life and activities of daily life.11, 12, 13 Preliminary evidence indicates that higher CRF is associated with lower severity of symptoms (e.g., fatigue, dyspnea, quality of life, anxiety, depression) in individuals that had a symptomatic phase >12 weeks after contracting COVID-19.¹⁴

With >144 million cases worldwide, long COVID is arguably the next global health challenge that will continue to create a substantial burden for healthcare services.¹⁵ A number of individuals diagnosed with long COVID complain of reduced functional capacity and abnormal symptoms during physical exertion (e.g., dyspnea). Moreover, data are already emerging to demonstrate a significant reduction in CRF is a hallmark characteristic of long COVID.16, 17, 18 In this context, CRF assessment, ideally through CPET will become a vital tool in the baseline assessment of patients with long COVID, designing individualized exercise training programs, and longitudinally tracking improvements/recovery. Accordingly, we must take proactive approaches to protect population health and well-being and mitigate the impacts on physical and mental well-being.

In summary, the emerging body of evidence during the COVID-19 era reaffirms CRF assessment should be considered a vital sign,¹⁹ both from the perspective of assessing who is at higher risk for untoward events (e.g., chronic disease diagnosis and a complicated medical course with viral infection) and to characterize the long term effects of those who have been infected with COVID-19.

Impact of COVID-19 on physical activity (PA) levels

Physical inactivity is an established risk factor for CVD and is associated with lower levels of CRF. As such, high levels of PA and exercise training are key components for developing high CRF and improving one's health trajectory. Thus, it is unfortunate that a consequence of the lockdown and restrictions enacted during the COVID-19 pandemic was reduced PA, which has been well documented to impact physical and mental well-being.²⁰ Ammar et al.²¹ reported a decline in all PA intensity levels (vigorous, moderate, walking and overall) and Barbieri et al.²² reported a decline from an average of ∼10,000 steps/day taken pre-pandemic to ∼4600 steps/day during the first couple months of the pandemic. Further, daily sitting time has increased from 5 to 8 h/day,²¹ with the added time spent performing predominately screen-based sedentary behaviors, which are correlated with CVD risk factors.

Higher levels of PA appear to be protective against severe outcomes from COVID-19 as Sallis et al.²³ reported in a population of 48,400 adults diagnosed with COVID-19 that those who were consistently inactive had a higher risk of hospitalization, need for intensive care treatment, and death. In fact, because of the convincing evidence linking physical inactivity to a higher risk of untoward events with SARS-CoV-2 infection, the CDC now recognizes physical inactivity as a “medical condition” that increases the risk for “getting very sick from COVID-19”.²⁴ Physical inactivity acutely influenced health outcomes during the pandemic and the prolonged effects of reduced PA may be manifest by increased risk for CVD in the future as well as poor preparation for future viral pandemics. Therefore, there is a need to restore and increase PA levels, which will lead to improvements in CRF as summarized nicely in an Infographic by Smirmaul and Arena.²⁵ One of the positive adaptations from COVID-19 is the development of more home-based and virtual exercise programming options.²⁶ These options allow individuals to be more physically active by overcoming traditional barriers such as transportation, scheduling conflicts due to occupational or personal requirements, and expenses. Considering the importance of higher levels of CRF, health professionals need to accelerate the promotion of increasing PA and exercise training, which will therefore improve CRF and provide protection as the pandemic progresses towards its endemic phase.

Widespread determination of CRF

A Scientific Statement from the American Heart Association recognizes that the gold standard for directly assessing CRF is CPET.² Nonetheless, to encourage the practice of CRF determination when CPET is not feasible, several other assessment procedures that calculate an estimated CRF (eCRF) are recommended. Research indicates some of these eCRF assessments are related to health outcomes and can produce similar group means to directly-measured CRF.^{2 ,} 27, 28, 29, 30, 31, 32, 33 However, the degree of error associated with eCRF suggests these assessments should be used with caution when evaluating an individual in clinical settings.

The simplest determination of eCRF involves the use of a non-exercise prediction equation. Non-exercise prediction equations are an easy and inexpensive method for assessing CRF because exercise is not required, and the needed information is typically available in electronic medical records. There are over 30 non-exercise equations that are based on the relationship between CRF and characteristics such as age, sex, height, and weight.^{31 , 33} Many of these equations also include self-reported physical activity status to further improve predictions of CRF. Non-exercise prediction equations are not without limitations though. These prediction equations do not account for important factors such as the genetic influence on CRF³⁴ and social desirability biases that can influence the self-reported variables (e.g., PA levels³⁵). Furthermore, while a non-exercise prediction equation has recently been created for those with CVD³⁶, the majority of equations have largely been developed from cohorts of apparently healthy adults, meaning they are less accurate at the lower and upper ends of the CRF spectrum.^{2 , 37} This is particularly problematic for the CVD population who predominantly have a CRF well below age- and sex- predicted normative values.³⁸ As such, the use of these equations can lead to overestimations of CRF³⁶ and may reduce the ability to stratify their health risk in patient populations.

Other methods of assessing eCRF involve either submaximal or maximal exercise testing without direct measurement of ventilatory expired gas (i.e., without CPET), and are regarded as being more accurate because they account for individual-specific exercise responses.² For submaximal testing, two submaximal steady-state work rates are typically performed with a regression equation of the work rate and heart rate response used to extrapolate to a predicted maximal effort. There are significant limitations associated with this extrapolation though, due to individual differences in mechanical efficiency and the error associated with predicting maximal heart rate (HR).^{2 , 39 , 40} Estimations from maximal exercise testing are more common clinically and typically use the total test duration or peak workload to determine eCRF. Potential sources of error still exist with these maximal test estimations, such as workload adjustments from one stage to the next that are too aggressive.² Of note, the error associated with many of the exercise-based prediction equations is similar to that observed with non-exercise prediction equations,³² suggesting exercise tests should involve CPET to improve clinical utility.

The ease of determining eCRF makes it a valuable tool in research settings when CPET is not practical or feasible. However, in a clinical setting where the focus is on the individual instead of the population, the accurate assessment of CRF is essential. Recent research has highlighted limitations associated with stratifying individuals using single^{32 , 33 , 36} or longitudinal³¹ eCRF measures. Thus, when direct measures of CRF are not available, eCRF should only be considered as an initial guide used in combination with patient symptoms and medical history to stratify risk and improve clinical care.

CPET during the COVID-19 era

The established health benefits of higher CRF levels as it relates to improving outcomes in those infected with COVID-19 provide further support for the clinical use of CRF in patient care. Although CRF can be estimated, it is most accurately measured by CPET, which has gained broad recognition within healthcare settings.⁴¹ CPET is used primarily to evaluate the integrative response to incremental exercise, enabling an objective insight into CRF and reasons for physical impairment⁴² as well as determining therapeutic efficacy. As well as characterizing CRF, CPET plays an integral role in clinical arenas including determining surgical operability and evaluating the risk of perioperative death and post-operative complications,⁴³ supporting pre-operative planning algorithms,⁴⁴ developing management strategies for pathological conditions (e.g. CVD)⁴⁵ and in disease prognostication (e.g., pulmonary hypertension).⁴⁶

During the initial stage of the COVID-19 pandemic, routine clinical practices, including CPET were curtailed as clinical assessments and investigations were restricted and staff were repositioned to other clinical areas to address the burden of the pandemic in acute and critical care clinical settings.⁴⁷ Despite the transition towards endemic status, there remains a level of uncertainty regarding the ability to safely undertake CPET procedures given concerns around patients and staff safety due primarily to human respiratory aerosols that are important in the transmission of viral pathogens.⁴⁸ Several papers have established responses to the challenges around delivering CPETs^{47 , 49} and other lung function assessments⁵⁰ alongside the guidelines produced by a number of governing bodies and associations.⁵¹ Despite the highlighted risks that remain prevalent due to sustained transmission and the threat of emerging variants, CPET remains an integral investigative tool in clinical practice and consideration for how these can be restored in the post-COVID-19 phase is crucial, particularly given the value of CPET in the new long COVID patient population.

Prior the COVID-19 pandemic, CPET was a highly relevant investigative and diagnostic tool and will undoubtedly have an important role in evaluating individuals recovering from severe COVID-19 infection. CPET provides an ideal approach to assessing the intersection between pathophysiologic and clinical manifestations, allowing for a refined account of the impact the viral infection has both cross-sectionally and longitudinally (acknowledging the prevalence and increase in long COVID diagnosis), most importantly during a bout of physical exertion in a controlled environment. Without this insight, the impacts of COVID-19 that manifest during physical activity, or manifest more profoundly during physical exertion, would be missed entirely, preventing a holistic understanding of the clinical presentation.⁴² In this context, estimating CRF would have less value and measurements obtained from an assessment of cardio-respiratory responses to physiological stress (i.e., CPET) could provide insight regarding the integrity of the pulmonary-vascular interface and characterization of any impairment or abnormal cardio-respiratory function which can be used to support the development of bespoke and informed rehabilitation approaches that can restore observed reductions in physical capacity and functional status¹³. Confirmation of hypercoagulation and micro clots in the base of the lungs of patients with poor disease outcomes following a COVID-19 infection,⁵² highlight the need for investigative and diagnostic approaches to outline and address inhibited alveolar ventilation, oxygen exchange and functional status.

The importance of CPET in clinical domains has increased as a result of the COVID-19 pandemic and there is a need to respond to increased pressure on healthcare settings owing to the volume of routine clinical appointments and procedures that were curtailed to prioritize the burden in the earlier stages of the pandemic.⁵³ A solution to ease the burden on clinical services might be to establish collaborative links with exercise science and medical specialists with expertise in human physiology and experience in CPET procedures⁵⁴ to facilitate mass testing, which could include the use of sports and exercise departments within university settings that are well equipped to deliver such activity⁵⁵ Guidelines clearly describe CPET procedures, equipment maintenance and calibration as well as demonstrated competencies required for personnel conducting an exercise test. These guidelines should be closely followed and adhered to by all CPET laboratories56, 57, 58, 59 in order to ensure safe, valid and reliable tests are performed.

Summary

The COVID-19 pandemic has illuminated the pervasiveness of unhealthy lifestyle characteristics and resultant health consequences, which are most prevalent in vulnerable and underserved populations. The severe health-related impact of the pandemic highlights the need for widespread policy changes that place focus on prevention. CRF is a well-established biomarker that is strongly related to the development of CVD risk factors and the benefits of CRF are ubiquitous across race, ethnicity, and socioeconomic status.^{1 , 2} Previous research has established the association between CRF and risk for chronic disease and COVID-19 has highlighted that CRF levels also influence outcomes from infectious disease. Thus, increasing awareness of and the clinical utilization of CRF will undoubtedly have far-reaching health benefits. In addition to being the gold standard method of assessing CRF, CPET has many clinical uses and will be a key tool in detecting and understanding the pathophysiology of the lasting effects of COVID-19. The post-COVID-19 era is an opportune time for an increased focus on CRF, PA, and the exercise sciences as a core approach to preventing future health crises.⁵⁵

Declaration of Competing Interest

None.