Image description: a man is on an exercise bike with leads and an oxygen mask attached to him. Inset picture shows a test tube with blood and plasma. The title reads Study uncovers reduced exercise tolerance and other changes in Long Covid. ME Association logo (bottom right)

Study uncovers reduced exercise tolerance and other changes in Long Covid

A recent study published in Pulmonary Circulation assesses changes in oxygen extraction following Long Covid. This condition may affect half of patients who recover from a Covid-19 infection, and one debilitating hallmark is a persistent decrease in exercise tolerance.

ME Association comment

“This is an interesting study that adds to our knowledge of Long Covid and what might be underlying symptoms such as debilitating fatigue and post-exertional malaise. These results are remarkably similar to the outcomes we have seen in ME/CFS research, once again showing there are close similarities in both of these ‘post-viral fatigue syndromes'.

Russell Fleming
Head of Communications. The ME Association.


While prior studies have shown dysregulated alterations in the immune system following COVID-19 infection, no study to date had associated such findings with the impaired oxygen extraction that may be a critical driver of persistent exertional intolerance in long COVID patients.

“We previously demonstrated on invasive cardiopulmonary exercise testing (iCPET) that the pathophysiologic abnormality in patients with [Long Covid] was a primary peripheral limit to exercise characterized by impaired or systemic oxygen extraction,” states Singh. “This current study combined our iCPET capability with an unbiased proteomic analysis to better understand why [Long Covid] patients experience this impaired oxygen extraction phenomenon.”

The authors identified two subsets of PASC patients: those with mild reduction in the body's ability to extract oxygen from the blood, and those with severe reduction in oxygen extraction capacity.

Multiomic proteomic analysis of blood collected from these patients identified increased circulating levels of proteins implicated in the inflammatory and fibrotic processes among the PASC patients with severely-reduced oxygen extraction capacity, as well as increased levels of proteins associated with endothelial dysfunction, or the inner layer of blood vessels critical for normal function of the lungs in extracting oxygen.

Singh states, “The current study shows that there exists a dichotomy of cardiopulmonary and proteomic phenotype that begets the observed impaired systemic oxygen extraction in PASC. These distinct cardiopulmonary proteomic phenotypes can help foster future studies to develop a personalized medicine approach for the different PASC phenotypes.”

Chun adds, “These findings not only identify new mechanisms that may help identify those patients most likely to develop persistent long COVID symptoms, but also identify disease mechanisms that may be potentially targeted to improve the long COVID symptoms.”

Research abstract

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET).

However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value.

Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001).

PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated.

In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. 

PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

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