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. 2023 Apr 17;313:104062. doi: 10.1016/j.resp.2023.104062

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

Anna Norweg a,⁎, Lanqiu Yao b, Scott Barbuto a, Anna S Nordvig c, Thaddeus Tarpey b, Eileen Collins d, Jonathan Whiteson e, Greg Sweeney e, Francois Haas e, John Leddy f
PMCID: PMC10108551  PMID: 37076024

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.

Keywords: Long COVID-19, Energy metabolism, Chronotropic intolerance, Post-exertional malaise, Exercise intolerance, Dysautonomia

1. Introduction

Long COVID-19 occurs in approximately 10 – 20% of survivors of COVID-19, representing about 10 – 20 million global long-term cases (Vehar et al., 2021, Wise, 2021). It is characterized by persistent, multi-organ symptoms beyond 3 months from onset of acute illness.(Soriano et al., 2021) Chronic fatigue, exercise intolerance, post-exertional malaise (PEM), and orthostatic intolerance are some of the more debilitating symptoms of long COVID-19. Exercise intolerance is defined as the “inability to exercise to near age-appropriate maximum heart rate due to exacerbation of symptoms”.(Leddy et al., 2021),p.3 PEM is defined as “inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, tendency for symptoms to worsen, or prolonged exacerbation of patient’s baseline symptoms after physical, cognitive, and orthostatic stress” (Jason et al., 2021), p.238 PEM symptom exacerbation can be immediate after exertion or can be delayed for 24–72 h.

Underlying mechanisms of exercise intolerance in the chronic or "long-hauler" phase of COVID-19 are likely multifactorial. Impaired mitochondrial function (regulation of energy metabolism) and oxygen metabolic homeostasis (e.g., oxygen transportation and sensing) may be a significant contributing factors to fatigue and impaired exercise tolerance in long COVID (Astin et al., 2023). Impaired autonomic nervous system (ANS) function can result in dysregulated heart rate, blood pressure, respiratory, gastrointestinal, thermoregulatory, and bladder functions. Exercise intolerance may be associated with blunted or decreased age-predicted maximal heart rate (HR), also called chronotropic intolerance (CI). CI is diagnosed by inability to meet 80% of age-derived HRpeak during a noninvasive maximal cardiopulmonary exercise testing (CPET) (Jimeno-Almazán et al., 2021). The aim of our observational, retrospective study was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies.

2. Methods

Patients recovered from positive, acute COVID-19 infection and referred for cardiopulmonary exercise testing (CPET) at an urban Ambulatory Care Center, between March and August 2020, were included in a COVID-19 Survivorship Registry. Inclusion criteria were at least 21 years of age with positive COVID-19 infection in electronic medical record. Participants’ exercise capacity was compared to reference normative data. Statistical differences in the cohort were calculated between patient sub-groups based on standard % predicted peak oxygen consumption (VO2 peak). To diagnose CI, we analyzed a subgroup of patients who completed a maximal CPET (defined by an RER peak >1.05 (Radtke et al., 2019)) and who were not admitted to ICU (Davenport et al., 2019). RER is VCO2/VO2 (ATS/ACCP, 2003). We also compared subgroups based on gender, since long COVID-19 may be more prevalent in women (Torjesen, 2021).

We evaluated lung function with spirometry and exercise capacity using gold standard CPET on a treadmill (Vyaire Medical, Mettawa, IL) with the Bruce protocol (Myers et al., 1991). In particular, we used the 2012 European Respiratory Society Global Lung Function Initiative’s (GLI) prediction equations, with age- and gender-dependent lower limits of normal and validity across different ethnic groups, to calculate lung volume, diffusion, spirometry, and exercise capacity values.(Quanjer et al., 2012)

Past medical history data were collected, including hospital length of stay, need for intensive care unit (ICU), and mechanical ventilation. Quantitative demographic and clinical variables were evaluated using Student's t-test or a Wilcoxon Rank Sum test, depending on whether the given variable was normally distributed. The Shapiro-Wilk test was used to examine the normality of each quantitative variable. Pearson's Chi-square test was used to assess qualitative variables such as gender and race. Statistical significance was considered as a p-value of < 0.05. The statistical analysis was conducted with R-3.5.1.a.

Normal exercise capacity was defined as VO2peak > 84% predicted, (ATS/ACCP, 2003) and > 80% predicted for other exercise parameters (ATS/ACCP, 2003) We hypothesized that exercise intolerance was associated with impaired oxygen extraction, autonomic dysfunction, and deconditioning in patients with long COVID-19.

3. Results

We collected CPET data on 59 long COVID-19 participants (34 men, 58%) with a mean (SD) age of 53.9 years (15.0). Average (SD) days after positive infection diagnosis was 167 (68.8). 56% of participants had been hospitalized with acute COVID-19, 42% of whom required ICU. 87% of patients in ICU required mechanical ventilation. 82.6% of patients admitted to ICU received inpatient pulmonary rehabilitation compared with only 6.2% of patients hospitalized without ICU stay (p < 0.001). Race was a significant social determinant of whether a patient was admitted to the ICU (p = 0.024). Except for forced vital capacity (FVC), which was an average of 74% predicted (range: 64–90), mean spirometry values were normal in our sample.

Mean (SD) O2 pulse peak % predicted was 79 (12.9) ( Table 1). Test duration was 79.6 (22.3) % predicted (Table 1). Mean % predicted HRpeak was ≤ 75%. 24 participants (41%) had reduced exercise capacity, defined by a VO2 peak ≤ 84% (ATS/ACCP, 2003). Mean VO2 peak was 89.2% (SD = 22.2%). 18 participants (30.5%) showed high (≥34) VE/Vco2 slope.

Table 1.

Differences based on VO2 Maximum Exercise Capacity Criterion.

Total Sample VO2 peak > 84% pred VO2 peak ≤ 84% pred p-value
n (%) 59 35 (59) 24 (41)
Age, years 53.9 (15) 54.7 (15.8) 52.7 (14) 0.61
Sex (%) 0.371
Male 34 (57.6) 18 (51.4) 16 (66.7)
Female 25 (42.4) 17 (48.6) 8 (33.3)
Race (%) 0.183
White 29 (50.0) 21 (61.8) 8 (33.3)
African American 10 (17.2) 5 (14.7) 5 (20.8)
Asian 5 (8.6) 1 (2.9) 4 (16.7)
Chinese 2 (3.4) 2 (5.9) 0 (0.0)
Filipino 4 (6.9) 2 (5.9) 2 (8.3)
Latino 6 (10.3) 2 (5.9) 4 (16.7)
Other 2 (3.4) 1 (2.9) 1 (4.2)
Weight loss post-COVID-19 (lbs.) 14.4 (14.3) 17.4 (14.4) 15 (14.5) 0.457
Hospitalized (%) 32 (56.1) 18 (52.9) 14 (60.9) 0.749
Inpatient rehabilitation (%) 21 (36.8) 12 (35.3) 9 (39.1) 0.988
ICU (%) 23 (41.8) 12 (37.5) 11 (47.8) 0.625
Mechanical ventilation (%) 20 (36.4) 11 (34.4) 9 (39.1) 0.938
Days from hospital discharge 69 (57–143) 64 (55.2–98) 125 (69–146) 0.211
Days from positive COVID-19 test diagnosis 167 (68.8) 159.3 (68.1) 177.8 (70) 0.332
Length of stay, days 38.1 (26.9) 32.8 (23.2) 44.9 (30.7) 0.249
Days in ICU 13.5 (10.3) 12.9 (11.4) 16 (5.7) 0.614
FVC % pred 74 (64–90) 80 (69–94) 63.5 (54.2–81.5) 0.003
FEV1% pred 82.2 (18.5) 88.1 (15.9) 73.6 (18.8) 0.004
FEV1/FVC 85.2 (8) 84.5 (7.7) 86.3 (8.4) 0.407
PEF % pred 95 (83.5–106.5) 102 (91–110) 85 (77–95) 0.001
FEF 25–75% 100 (82.5–118.5) 102 (85.5–118.5) 96.5 (80.2–117) 0.436
Performance
VO2peak (ml/kg/min) 21.8 (6.1) 24.3 (5.2) 18.2 (5.6) < 0.001
VO2peak (ml/kg/min) % pred 89.2 (22.2) 104.2 (12.5) 67.4 (13.1) < 0.001
VO2 AT (ml/kg/min) 12.2 (3) 13.3 (2.7) 10.6 (2.7) < 0.001
Anaerobic threshold (AT/predicted VO2 max x 100) 57.4 (8.8) 55.7 (8.1) 50.0 (9.2) 0.069
Actual MET 6.2 (1.7) 7 (1.5) 5.2 (1.6) < 0.001
MET pred 7.7 (2.8) 8.6 (2.4) 6.5 (2.8) 0.004
Test Duration (n = 38) 7.44 (1.92) 7.88 (1.84) 6.41 (1.76) 0.031
Test Duration % pred (n = 38) 79.60 (22.26) 87.85 (20.55) 60.10 (11.55) < 0.001
Circulation
Peak systolic 162.4 (24.2) 168.7 (23.4) 153.2 (22.7) 0.017
Peak diastolic 80 (70–80) 80 (70–80) 70 (66–80) 0.242
HR reserve (beats/min) 16 (3.5–27.5) 6 (0–17.5) 27 (17–44.5) < 0.001
HR peak 149.2 (23.1) 156.7 (19) 138.3 (24.5) 0.004
HR % pred 89.8 (11.4) 94.9 (9.2) 82.3 (10.4) < 0.001
HR AT 105.9 (14.9) 107.8 (13.4) 103.2 (16.7) 0.267
HR peak % pred 71.5 (8.3) 69.1 (7.5) 75 (8.2) 0.007
Cardiovascular Function
Peak VO2/HR 11.6 (9.9–13.7) 12.4 (10.9–14.4) 10.7 (9.1–11.9) 0.002
O2 pulse peak % pred 79 (12.9) 78.6 (13.7) 79.5 (11.7) 0.772
VO2/HR AT 9.4 (2.7) 10.3 (2.7) 8.2 (2.2) 0.002
VO2/HR % pred 99.3 (21) 110.6 (13.5) 82.8 (19) < 0.001
Rate-pressure product (RPP) 22,700 (18,186–26767.5) 23,940 (22,176–28730) 18,144 (15,865–23430) < 0.001
Ventilation
Peak VE (L/min) 71.5 (24.4) 80.2 (22) 58.8 (22.4) < 0.001
VE % pred (SD) 81 (21.3) 87.1 (18.6) 72 (22.3) 0.009
VE reserve (range) 18 (4–29.5) 17 (0–24.5) 23 (5.8–37.2) 0.107
Gas exchange
VE/VCo2 AT 31.8 (29.1–35.6) 31.6 (28.6–34.6) 32.5 (29.9–38.7) 0.208
RER peak 1.11 (0.12) 1.13 (0.10) 1.08 (0.13) 0.099
SpO2 minimum 95 (94–97) 95 (94–97) 95 (92.8–98) 0.938
Open in a new tab

Note. AT: at threshold. HR: heart rate. Lbs: pounds. FVC: forced vital capacity. Min: minutes. O2: oxygen; PEF: peak expiratory flow. pred: predicted. RER: respiratory exchange ratio at end of test. RPP: rate-pressure product. VE: minute ventilation. VE/VCo2 AT: ventilatory equivalent for carbon dioxide. VO2: oxygen uptake; VO2/HR: oxygen pulse. VE/VCO2 ratio: ventilatory equivalent for carbon dioxide.

Reduced exercise capacity defined as VO2 peak ≤ 84% pred. Normal exercise capacity defined as VO2 peak > 84% predicted.

Only 19 non-ICU participants completed a maximal CPET ( Table 2). Mean (SD) HRpeak was 69 (7.7) % predicted in this subsample (Table 2), indicating blunted rise in HR (CI, i.e., inability to meet 80% of age derived HRpeak) during a maximal CPET (n = 19).(Jimeno-Almazán et al., 2021) In participants who achieved peak volume of oxygen consumed (VO2)> 84%, mean HR peak % predicted was 65.5%, significantly below normative values.

Table 2.

Differences based on VO2Maximum in Patients with a Maximal CPET.

Total Sample VO2 peak > 84% pred VO2 peak ≤ 84% predicted p-value
n (%) 19 13 6
Age, years 54 (15.9) 52 (18.7) 58.3 (6.2) 0.287
Sex (%) 0.735
Male 9 (47.4) 7 (53.8) 2 (33.3)
Female 10 (52.6) 6 (46.2) 4 (66.7)
Race (%) 0.105
FVC % pred 79.8 (15.8) 85.6 (12.9) 67.2 (14.8) 0.028
FEV1% pred 85.4 (14) 91 (9.6) 73.3 (15.1) 0.035
FEV1/FVC 84.3 (6.8) 83.5 (6.1) 85.8 (8.5) 0.57
PEF % pred 98 (17.5) 104.4 (16.8) 84.2 (9.3) 0.004
Performance
VO2peak (ml/kg/min) 22.6 (7.2) 25.4 (6.2) 16.4 (5.4) 0.008
VO2peak (ml/kg/min) % pred 100 (78–106) 105 (100–108) 72 (58–75.5) < 0.001
VO2 AT (ml/kg/min) 12.1 (3.8) 13.5 (3.4) 9.1 (2.8) 0.012
VO2 AT/peak % pred 54.5 (9.8) 53.5 (9.3) 56.8 (11.2) 0.500
Actual MET 6.4 (2.1) 7.2 (1.8) 4.7 (1.5) 0.011
MET pred 7.9 (3.4) 8.9 (2.9) 5.7 (3.5) 0.083
Test Duration (n = 15) 7.8 (2.3) 8.3 (2.0) 4.5 (0.0) 0.019
Test Duration % pred (n = 15) 86.5 (23.4) 91.4 (20.9) 54.8 (9.9) 0.033
Circulation
Peak systolic 154.2 (22.8) 159.7 (24.3) 140 (9.4) 0.025
Peak diastolic 71 (70–80) 72 (70–80) 70 (70–72) 0.644
HR reserve (beats/min) 16 (2–25.5) 5 (0–16) 33 (25.2–46.8) 0.002
HR peak 150.3 (24.3) 161.5 (19.7) 126 (12.9) < 0.001
HR % pred 90.4 (10.9) 96.1 (6.7) 78.2 (7.4) < 0.001
HR AT 102.6 (13.6) 105.2 (14.4) 97 (10.5) 0.183
HR peak % pred 69 (7.7) 65.5 (6.3) 76.7 (4) < 0.001
Cardiovascular Function
Peak VO2/HR 11.9 (10.1–13.7) 11.9 (10.7–13.8) 11.2 (9.7–13.3) 0.483
O2 pulse peak % pred 77.4 (18.9) 79.9 (19.6) 72 (17.4) 0.396
VO2/HR AT 9.9 (8.8–11.4) 11.1 (9.3–11.9) 9.4 (6.8–9.9) 0.105
VO2/HR % pred 100.9 (15.6) 107.1 (10.7) 87.7 (17.1) 0.039
Rate-pressure product (RPP) 22,764 (17,503.5–27654) 25,110 (22,680–29070) 17,082 (14,850–17290) 0.008
Ventilation
Peak VE (L/min) 80.2 (24.2) 87.3 (25.1) 64.7 (13.3) 0.02
VE % pred 86 (19.5) 88.5 (20.2) 80.5 (18.1) 0.405
VE reserve (L/min) 14 (2–24.5) 17 (0–24) 10.5 (4–26) 0.86
Gas exchange
VE/VCo2 AT 33.4 (7.8) 31.3 (6.8) 38 (8.4) 0.122
RER peak 1.2 (0.1) 1.2 (0.1) 1.1 (0.03) 0.004
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Note. AT: Anaerobic threshold. HR: heart rate. Lbs: pounds. FVC: forced vital capacity. Min: minutes. O2: oxygen; pred: predicted. PEF: peak expiratory flow. RER: respiratory exchange ratio at end of test. RPP: rate-pressure product. VE: minute ventilation. VE/VCo2 AT: ventilatory equivalent for carbon dioxide. VO2: oxygen uptake; VO2/HR: oxygen pulse. VE/VCO2 ratio: ventilatory equivalent for carbon dioxide.

Reduced exercise capacity defined as VO2 peak ≤ 84% pred. Normal exercise capacity defined as VO2 peak > 84% predicted.

Analyzing by sex, only women with reduced exercise capacity (VO2 peak ≤84% pred) had higher mean VE/Vco2 slope of 38.8 at the anaerobic threshold (p = 0.049) compared with women demonstrating normal exercise capacity, which may reflect hyperventilation and ventilatory inefficiency (n = 25). In women only, mean (SD) peak respiratory exchange ratio (RERpeak) – the ratio of carbon dioxide metabolic production to oxygen uptake – of 1.0 (0.1) was reduced in the reduced exercise capacity subgroup compared with 1.1 (0.1) in normal exercise capacity subgroup, indicating sub-maximal effort and exertion intolerance (p = 0.038).(10JR: ATS/ACCP Statement on cardiopulmonary exercise testing Am. J. Respir. Crit. care Med. 167 2 2003 211 277 ATS/ACCP Statement on cardiopulmonary exercise testing. American journal of respiratory and critical care medicine. 2003;167(2):211–277., Kim et al., 2016) In contrast to women, reduced exercise capacity was associated with worse pulmonary function values (FVC % pred, p = 0.032; FEV1% pred and PEF % pred, p = 0.025) only in men, suggesting more severe COVID-19 disease and/or premorbid comorbidity in men.

4. Discussion

This observational study explored contributing factors to exercise intolerance in symptomatic patients with a mean of 6 months post-acute COVID-19 infection. We found a circulatory limitation (mean HRR <15 beats/min)(TS/ACCP,. 2003) in the VO2 peak > 84% predicted group. We also found mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced in our sample (n = 59). O2 pulse reflects the “amount of O2 extracted per heartbeat”.15,p. 212; 10 O2 pulse is equal to the product of stroke volume and the arterial-to-mixed venous O2 content difference [C(a–v)O2] (ATS/ACCP, 2003). We hypothesize that this impaired circulation and O2 extraction, and low O2 pulse (and likely lactic acid accumulation) contributed to early mental and peripheral muscle fatigue and early exercise termination. Impaired energy metabolism and mitochondrial bioenergetics as a mechanism of impaired exercise tolerance in long COVID is novel and similar to ME/CFS (Guntur et al., 2022). Our finding of CI – an indication of impaired autonomic function – may further explain persisting symptoms of long COVID, such as dyspnea and PEM; (Davenport et al., 2019) consistent with another long COVID-19 study (Balady et al., 2010, Jimeno-Almazán et al., 2021).

In our cohort, heart rate (HR) reserve was significantly higher in the reduced exercise capacity subgroup (those with VO2 peak ≤84% predicted), possibly also indicating deconditioning. These participants demonstrated less energy expenditure (METs), shorter test duration, and higher heart rate reserve (1 −(peak heart rate/(220 −age))× 100; Table 1.

Mean VE reserve (VEmax /MVV) × 100) was 10.5 (4−26) for patients with VO2 peak ≤ 84% predicted (in maximal CPET, Table 2), possibly also contributing to exercise intolerance and lower RER. A VE reserve of ≥ 15% of ventilatory capacity is considered normal (ATS/ACCP, 2003) Almost a third of subjects showed breathing inefficiency, defined as high (≥34) VE/Vco2 slope (Balady et al., 2010). Therefore, a ventilatory limitation may be a contributing factor to exercise intolerance in long COVID.

While a gold standard for defining maximal effort does not exist, a majority (57.6%) of subjects did not meet normative criteria for a maximal test, i.e., RERpeak (>1.05) supporting suboptimal effort. Our findings highlight exertional limitation and a high prevalence of early exercise termination in patients with long COVID-19. Consistent with our hypotheses, exertional limitation may be associated with autonomic dysfunction (CI, reduced peak systolic pressure, and breathing inefficiency) in adults with long COVID. Suboptimal effort (submaximal tests) was supported by another long COVID study (Motiejunaite et al., 2020).

A single administration of CPET may overestimate the exercise tolerance of patients with long COVID-19 because patients with PEM may not be able to reproduce exercise performance 24 h later (Nelson et al., 2019). We therefore recommend a more comprehensive evaluation of post-exercise recovery with 2-day CPET.

4.1. Limitations

A limitation of our study is that we did not collect data on comorbid medical conditions or quantify symptoms. However, all participants were symptomatic at the time of CPET testing. Timing of CPET varied widely for days post-positive COVID-19 test. Diffusing lung capacity for carbon monoxide (DLCO) data was not measured as a contributing factor in exercise intolerance. Impaired DLCO can persist in adults with long COVID and is associated with symptoms of exertional dyspnea.(Fortini et al., 2022) The heterogeneity of the sample (with the inclusion of both patients post-ICU with mechanical ventilation and those after only mild COVID-19 infection) limited the interpretation of our findings and our ability to characterize patients’ ventilatory capacity. We also did not repeat CPET within 24 h to assess PEM and determine subjects’ ability to reproduce VO2 peak.

5. Conclusions

Impaired oxygen extraction, stroke volume (O2 pulse), and CI were associated with long COVID. Impairments of O2 uptake, delivery, and ventilation may contribute to persisting symptoms of long COVID-19, especially fatigue, post-exertional malaise, and dyspnea. Our study may help to advance understanding of biomarkers in long COVID and assist with the development of effective treatments. Considering exercise as medicine, (Oliveira and Hood, 2019) by improving oxygen metabolism and mitochondrial bioenergetics, tailored sub-symptom, low-intensity aerobic exercise may provide the right stimulus to help to treat long COVID (Guntur et al., 2022, Sorriento et al., 2021, Heo et al., 2023). Exercise improves nitric oxide, a potent vasodilator with anti-coagulant, antiviral, and antioxidant effects (Ricciardolo et al., 2020, Maiorana et al., 2003).

Supplier

R Core Team, 2022; The R Foundation.

Ethics approval

This study was approved by New York University’s Institutional Review Board (i20–00909).

Study design

A. Norweg, L. Yao, T. Tarpey; data analyses: L. Yao and T. Tarpey; interpretation of the results: A. Norweg, S. Barbuto, A. Nordvig, E. Collins, and J. Leddy; manuscript writing: A. Norweg, S. Barbuto, A. Nordvig, E. Collins, J. Leddy, L. Yao, T. Tarpey, J. Whiteson, G. Sweeney, and F. Haas.

Funding

This research did not receive any specific grant funding.

Conflict of interest statement

Authors have no conflicts of interest to report.

Acknowledgements

We acknowledge the assistance of Rany Condos, MD, in developing a Registry of COVID-19 Survivors and obtaining IRB approval of this study at New York University Grossman School of Medicine.

Data Availability

The authors do not have permission to share data.

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