Fatigue following COVID-19 infection is not associated with autonomic dysfunction

Abstract

Background: The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients.

Methods: We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing's autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results.

Results: We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety.

Conclusions: These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Results of Ewing’s autonomic battery.

Results of autonomic testing of fatigued and non-fatigued patients. (A) deep breathing (B) cold pressor test (C) Valsalva heart rate ratio (D) Valsalva blood pressure ratio (E) heart rate variability. T-test was used to assess differences in deep breathing and heart rate variability. Wilcoxon rank-sum test used to assess differences in cold pressor and Valsalva tests. * p <0.05 ** p <0.01 ***p <0.001 ns = not significant.

Fig 2. Heart rate and blood pressure changes during active standing.

Variation in mean values and standard deviations of (A) systolic blood pressure (B) diastolic blood pressure (C) heart rate from 10 seconds prior to active stand to 180 seconds after active stand. T tests used to assess differences between cohorts at each 10-second timepoint.

Fig 3. Change in heart rate and blood pressure following an active stand.

Changes from baseline measurements in heart rate, systolic blood pressure and diastolic blood pressure shown at (A) 10 seconds and (B) 20 seconds. Rate of change from 10 seconds to 20 seconds in heart rate and blood pressure are shown in (C). Results at 40 seconds are shown in (D). T-tests and Wilcoxon rank-sum tests used to assess between-group differences. ns = not significant.

Fig 4. Near-infrared spectroscopy during active standing.

Percentage TSI during active standing, showing difference between baseline and (A) nadir in first 30 seconds (B) maximum overshoot (C) nadir at any point. T-test used to assess statistical difference. TSI = tissue saturation index. ns = not significant.