Persistence of fatigue in the absence of pathophysiological mechanisms in some patients more than 2 years after…, 2025, Baldassarre+

[SNT Gatchaman]

Persistence of fatigue in the absence of pathophysiological mechanisms in some patients more than 2 years after the original SARS-CoV-2 infection

Spoiler: Authors

Giovanni Baldassarre; Lucrezia Zuccarelli; Thomas Favaretto; Caterina Ursella; Andrea Palomba; Paulo Cesar do Nascimento Salvador; Emanuela Sozio; Ernesto Crisafulli; Massimo Imazio; Carlo Tascini; Bruno Grassi

Following an acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a substantial percentage of patients report the persistence of debilitating symptoms, often grouped in a syndrome termed ‘long COVID’. We sought to identify potential pathophysiological mechanisms responsible for the persistence, in some long COVID patients, of symptoms related to fatigue/exercise intolerance (excessive or early fatigue, excessive or early dyspnoea, muscle weakness, and myalgias) more than 2 years after the original infection.

Twelve patients who reported persistent symptoms (Long COVID group; 57 ± 6 years, mean ± SD), and 14 patients without the symptoms (Control group; 57 ± 8 years) were evaluated. An extensive series of measurements were performed to identify pathophysiological mechanisms potentially responsible for the symptoms.

In long COVID patients, all items evaluating quality of life (SF-36 questionnaire) had lower scores (P < 0.01) compared to control. The habitual level of physical activity, muscle size and strength, maximal aerobic power and the ventilatory thresholds, peak cardiac function, the mechanical efficiency of cycling, pulmonary kinetics, microvascular/endothelial function (hyperemic response in the common femoral artery during passive leg movements), skeletal muscle oxidative metabolism (peak fractional O2 extraction and muscle recovery kinetics by the repeated occlusions test, by near-infrared spectroscopy) were not different in the two groups. Evidence of ventilatory inefficiency was described in a subgroup of long COVID patients.

More than 2 years after the original SARS-CoV-2 infection, a discrepancy was observed between the persistence of debilitating symptoms of fatigue/exercise intolerance and the absence of several investigated pathophysiological mechanisms. The discrepancy may be due to factors that remain to be elucidated.

HIGHLIGHTS
What is the central question of this study?

Which pathophysiological mechanisms are responsible for the persistence, in some patients, seen more than 2 years after the original SARS-CoV-2 infection, of symptoms of fatigue/exercise intolerance?

What is the main finding and its importance?

A discrepancy was observed between the persistence of symptoms of fatigue/exercise intolerance (excessive or early fatigue, excessive or early dyspnoea on exertion, muscle weakness, and myalgias) and the absence of several investigated pathophysiological mechanisms. Symptoms may be attributable to other factors (i.e., psychological/neurological) that were not investigated.

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[SNT Gatchaman]

The present study has some limitations. The number of patients was relatively limited.

The inferences we made on symptoms and pathophysiological mechanisms apply only to the type of patient selected for the study, that is, patients tested more than 2 years after the first outbreak of the pandemic disease, originally affected by a relatively mild disease, and who underwent ≥2 vaccinations.

In the present study, we did not determine the presence of postexertional malaise, one of the cardinal and distinctive symptoms of myalgic encephalomyelitis/chronic fatigue syndrome, and a common symptom also among patients with long COVID (Appelman et al., 2024). It should be noted, however, that post-exertional malaise was not considered in several other recent papers dealing with long Covid syndrome (Colosio et al., 2023; Noureddine et al., 2023; Ramírez-Vélez et al., 2023; Singh et al., 2022; Szekely et al., 2021).

Non-invasive measurements were performed in the present study. The absence of muscle biopsies did not allow us to compare our patients with those followed by previous authors (Appelman et al., 2024; Colosio et al., 2023) who described, in long COVID patients tested after shorter follow-ups, dysfunctions of mitochondria and their respiratory function.

 

[Utsikt]

More than 2 years after the original SARS-CoV-2 infection, a discrepancy was observed between the persistence of debilitating symptoms of fatigue/exercise intolerance and the absence of several investigated pathophysiological mechanisms. The discrepancy may be due to factors that remain to be elucidated.

May be? If the factors you investigated can’t explain the differences, it has to be something else. But it might be too hard to outright admit that your research is probably irrelevant for these conditions?