Exercise intolerance associated with impaired oxygen extraction in patients with long COVID.

OBJECTIVE: Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. RESULTS: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

Post-Acute Sequelae of COVID-19: The Potential Role of Exercise Therapy in Treating Patients and Athletes Returning to Play.

Post-acute sequelae of coronavirus disease 19 (COVID-19) (PASC) describe a wide range of symptoms and signs involving multiple organ systems occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, representing a growing health problem also in the world of sport and the athletic population. Patients with PASC have new, returning, or persisting symptoms four or more weeks after the infection. Among the most frequent symptoms, patients complain of fatigue, dyspnea, exercise intolerance, and reduced functional capacity that interfere with everyday life activity. The role of exercise programs in PASC patients will be identified, and upcoming studies will establish the magnitude of their benefits. However, the benefits of exercise to counteract these symptoms are well known, and an improvement in cardiopulmonary fitness, functional status, deconditioning, and quality of life can be obtained in these patients, as demonstrated in similar settings. Based on this background, this review aims to summarise the current evidence about the PASC syndrome and the benefit of exercise in these patients and to provide a practical guide for the exercise prescription in PASC patients to help them to resume their functional status, exercise tolerance, prior activity levels, and quality of life, also considering the athletic population and their return to play and sports competitions.

Factors of Persistent Limited Exercise Tolerance in Patients after COVID-19 with Normal Left Ventricular Ejection Fraction.

Exercise intolerance de novo is one of the most common reported symptoms in patients recovering from the Coronavirus Disease 2019 (COVID-19). The present study determines etiological and pathophysiological factors influencing the mechanism of impaired exercise tolerance in patients during Long-COVID. Consequently, the factors affecting the percentage predicted oxygen uptake at peak exercise (%VO2pred) in patients after COVID-19 with a normal left ventricular ejection fraction (LVEF) were assessment. A total of 120 patients recovering from COVID-19 at three to six months after confirmed diagnosis were included. The clinical examinations, laboratory test results, echocardiography, non-invasive body mass analysis, and spiroergometry were evaluated. The subjects were divided into the following groups: study patients' group with worsen oxygen uptake (%VO2pred < 80%; n = 47) and control group presenting%VO2pred ≥ 80% (n = 73). ClinicalTrials.gov Identifier: NCT04828629. The male gender and the percent of total body water content (TBW%) were significantly higher in the study group compared to the control group (53 vs. 29%, p = 0.007 and 52.67 (±6.41) vs. 49.89 (±4.59), p = 0.02; respectively). Patients with %VO2pred < 80% presented significantly lower global peak systolic strain (GLPS), tricuspid annular plane systolic excursion (TAPSE), and late diastolic filling (A) velocity (19.34 (±1.72)% vs. 20.10 (±1.35)%, p = 0.03; 21.86 (±4.53) vs. 24.08 (±3.20) mm, p = 0.002 and median 59.5 (IQR: 50.0−71.0) vs. 70.5 (IQR: 62.0−80.0) cm/s, p = 0.004; respectively) compared to the controls. The results of the multiple logistic regression model show that (A) velocity (OR 0.40, 95%CI: 0.17−0.95; p = 0.03) and male gender (OR 2.52, 95%CI: 1.07−5.91; p = 0.03) were independently associated with %VO2pred. Conclusions: Men have over twice the risk of persistent limited exercise tolerance in Long-COVID than women. The decreased (A) velocity, TAPSE, GLPS, and hydration status are connected with limited exercise tolerance after COVID-19 in patients with normal LVEF.

Exertional desaturations after COVID-19: A case for PFO closure.

We present a case of a woman with past medical history notable for mild COVID-19 infection who presented with dyspnea on exertion, then developed progressively worsening exertional desaturations and was found to have a patent foramen ovale (PFO). Extensive cardiopulmonary testing revealed no clear alternate etiology for her symptoms. After much discussion, she underwent successful closure of the PFO with complete resolution of her symptoms and significantly improved exertional desaturation.

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Exercise Intolerance in Post-Acute Sequelae of COVID-19 and the Value of Cardiopulmonary Exercise Testing- a Mini-Review.

Coronavirus disease (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with systemic organ damage in the most severe forms. Long-term complications of SARS-CoV-2 appear to be restricted to severe presentations of COVID-19, but many patients with persistent symptoms have never been hospitalized. Post-acute sequelae of COVID-19 (PASC) represents a heterogeneous group of symptoms characterized by cardiovascular, general, respiratory, and neuropsychiatric sequelae. The pace of evidence acquisition with PASC has been rapid, but the mechanisms behind it are complex and not yet fully understood. In particular, exercise intolerance shares some features with other classic respiratory and cardiac disorders. However, cardiopulmonary exercise testing (CPET) provides a comprehensive assessment and can unmask the pathophysiological mechanism behind exercise intolerance in gray-zone PASC. This mini-review explores the utility of CPET and aims to provide a comprehensive assessment of PASC by summarizing the current evidence.

Rehabilitation Journey of a COVID-19 Survivor from Hospitalization to Follow-up: A Case Report of Progressive Lung Fibrosis

Progressive lung fibrosis, an enduring complication of COVID-19, affects lung function adversely, fatigue levels, exercise tolerance, and health-related quality of life, affecting more than 50% of the confirmed cases. Furthermore, the number of post-COVID survivors is steadily increasing, stipulating a need for early, safe, and effective post-COVID pulmonary rehabilitation (PR). A 62-year-old male diagnosed with viral pneumonitis with severe lung fibrosis post-COVID infection exhibited severe exercise intolerance during hospitalization. An 8-week supervised, structured PR program led to early weaning from oxygen support and improved patient's functional outcomes. Amelioration in the patient's clinical status was demonstrated by a 50% reduction in his fatigue levels and a three-fold change in his functional capacity. This case study highlights the importance of early initiation of PR in optimizing patient's health status and reducing any further functional limitations.

Pathophysiology and rehabilitation management of exercise intolerance in COVID-19 patients.

OBJECTIVE: This review aimed to explore the pathophysiology and rehabilitation management of exercise intolerance in COVID-19 patients. METHODS: We reviewed articles published in 2019-2021 using PubMed, Google Scholar, and CINAHL databases as an electronic database. Data obtained were pathophysiology and rehabilitation management of exercise intolerance in COVID-19 survivors. Types of the article were original articles and systematic or narrative reviews, both published and preprint articles. Articles that were written in English and freely accessible in pdf or HTML format were included. RESULTS: There were 28 articles eligible for this review. Pathophysiology, rehabilitation management, and both pathophysiology and rehabilitation management were explained in 7, 24, and 4 articles, consecutively. DISCUSSION: Exercise intolerance is caused by some pathological processes in the respiratory, cardiovascular, and musculoskeletal systems as a result of systemic inflammation. Fatigue and shortness of breath during the activity were the most common symptom in the early phase of COVID-19 and persisted until the follow-up phase. Hospital admission, especially prolonged use of ventilators and immobilization worsen functional impairment resulting in persistent symptoms. Rehabilitation management begins with a functional assessment consisting of symptom assessment and physical examination of the body systems affected. The goals of rehabilitation management are to increase functional capacity, reduce symptoms, improve the ability to perform daily activities, facilitate social reintegration, and improve quality of life. Exercise is an effective intervention to reach these goals. Several studies recommend breathing, and aerobic exercises, as well as resistance exercises for peripheral and respiratory muscles, to improve symptoms and increase functional capacity.

From heart to muscle: pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection.

The long-term sequelae of the coronavirus disease 2019 (COVID-19) are multifaceted and, besides the lungs, impact other organs and tissues, even in cases of mild infection. Along with commonly reported symptoms such as fatigue and dyspnea, a significant proportion of those with prior COVID-19 infection also exhibit signs of cardiac damage, muscle weakness, and ultimately, poor exercise tolerance. This review provides an overview of evidence indicating cardiac impairments and persistent endothelial dysfunction in the peripheral vasculature of those previously infected with COVID-19, irrespective of the severity of the acute phase of illness. In addition, V̇o2peak appears to be lower in convalescent patients, which may stem, in part, from alterations in O2 transport such as impaired diffusional O2 conductance. Together, the persistent multi-organ dysfunction induced by COVID-19 may set previously healthy individuals on a trajectory towards frailty and disease. Given the large proportion of individuals recovering from COVID-19, it is critically important to better understand the physical sequelae of COVID-19, the underlying biological mechanisms contributing to these outcomes, and the long-term effects on future disease risk. This review highlights relevant literature on the pathophysiology post-COVID-19 infection, gaps in the literature, and emphasizes the need for the development of evidence-based rehabilitation guidelines.

Long term predictors of breathlessness, exercise intolerance, chronic fatigue and well-being in hospitalized patients with COVID-19: A cohort study with 4 months median follow-up.

BACKGROUND: Post-acute COVID-19 syndrome (PACS) is an emerging healthcare burden. We therefore aimed to determine predictors of different functional outcomes after hospital discharge in patients with COVID-19. METHODS: An ambidirectional cohort study was conducted between May and July 2020, in which PCR-confirmed COVID-19 patients underwent a standardized telephone assessment between 6 weeks and 6 months post discharge. We excluded patients who died, had a mental illness or failed to respond to two follow-up phone calls. The medical research council (MRC) dyspnea scale, metabolic equivalent of task (MET) score for exercise tolerance, chronic fatigability syndrome (CFS) scale and World Health Organization-five well-being index (WHO-5) for mental health were used to evaluate symptoms at follow-up. RESULTS: 375 patients were contacted and 153 failed to respond. The median timing for the follow-up assessment was 122 days (IQR, 109-158). On multivariate analyses, female gender, pre-existing lung disease, headache at presentation, intensive care unit (ICU) admission, critical COVID-19 and post-discharge ER visit were predictors of higher MRC scores at follow-up. Female gender, older age >67 years, arterial hypertension and emergency room (ER) visit were associated with lower MET exercise tolerance scores. Female gender, pre-existing lung disease, and ER visit were associated with higher risk of CFS. Age, dyslipidemia, hypertension, pre-existing lung disease and duration of symptoms were negatively associated with WHO-5 score. CONCLUSIONS: Several risk factors were associated with an increased risk of PACS. Hospitalized patients with COVID-19 who are at risk for PACS may benefit from a targeted pre-emptive follow-up and rehabilitation programs.

Exercise performance in patients with post-acute sequelae of SARS-CoV-2 infection compared to patients with unexplained dyspnea.

BACKGROUND: Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC. METHODS: We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era. FINDINGS: Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope. INTERPRETATION: Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2. FUNDING: The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542-02) from Harvard Catalyst.

Usefulness of physical function sub-item of SF-36 survey to predict exercise intolerance in patients with heart failure.

BACKGROUND: Exercise intolerance is widely known to be a major cardinal symptom in patients with heart failure (HF), but due to the recent coronavirus disease 2019 epidemic, it is still difficult to directly measure exercise tolerance in many hospitals and facilities. The 36-Item Short-Form Health Survey physical functioning (SF-36PF) pertain to lower extremity functioning and walking. The purpose of this study was to investigate whether SF-36PF is a useful predictor of exercise intolerance and to provide its optimal cut-off value for patients with HF. METHODS AND RESULTS: SF-36PF and 6-min walking distance (6MWD) were evaluated in 372 consecutive patients with HF. Exercise intolerance was defined at 6MWD cut-offs of 200, 300, and 400 m. The addition of SF-36PF to the pre-existing determinants of exercise tolerance significantly improved the area under the curve scores (0.85 vs. 0.89, P = 0.011 for 6MWD <200 m; 0.90 vs. 0.93, P = 0.001 for 6MWD <300 m; 0.88 vs. 0.90, P = 0.021 for 6MWD <400 m) for the predictive effect on exercise intolerance. The cut-off values of SF-36PF for predicting exercise intolerance defined by 6MWD <200, 300, and 400 m were 45, 50, and 70, respectively. CONCLUSIONS: SF-36PF is a useful tool as an alternative index to predict exercise intolerance in patients with HF.