Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.

Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (52.3%; 45/128) at 10 weeks (median) after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.

Background Persistent symptoms including breathlessness, fatigue and decreased exercise tolerance have been reported in patients after acute SARS‐CoV‐2 infection. The biological mechanisms underlying this ‘ Long COVID ’ syndrome remain unknown. However, autopsy studies have highlighted the key roles played by pulmonary endotheliopathy and microvascular immunothrombosis in acute COVID‐19. We hypothesized that endothelial cell activation may be sustained in convalescent COVID‐19 patients and contribute to Long COVID pathogenesis. Patients and Methods Fifty patients were reviewed at a median of 68 days following SARS‐CoV‐2 infection. In addition to clinical workup, acute phase markers, EC activation and NETosis parameters and thrombin generation were assessed. Results Thrombin generation assays revealed significantly shorter lag times (p<0.0001, 95% CI ‐2.57– ‐1.02min), increased endogenous thrombin potential (ETP) (p=0.04, 95% CI 15–416nM/min) and peak thrombin (p<0.0001, 95% CI 39–93nM) in convalescent COVID‐19 patients. These pro‐thrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including VWF:Ag, VWF propeptide (VWFpp) and Factor VIII (FVIII:C) were significantly elevated in convalescent COVID‐19 compared to controls (p=0.004, 95% CI 0.09–0.57IU/ml; p=0.009, 95% CI 0.06–0.5IU/ml; p=0.04, 95% CI 0.03–0.44IU/ml, respectively). In addition, plasma soluble thrombomodulin (sTM) levels were significantly elevated in convalescent COVID‐19 (p=0.02, 95% CI 0.01–2.7ng/ml). Sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization. Finally, both plasma VWF:Ag and VWFpp levels correlated inversely with 6‐minute walk tests. Conclusions Collectively, our findings demonstrate that sustained endotheliopathy is common in convalescent COVID‐19 and raise the intriguing possibility that this may contribute to Long COVID pathogenesis.

Rationale: Much is known about the acute infective process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease (COVID-19) pandemic. The marked inflammatory response and coagulopathic state in acute SARS-CoV-2 infection may promote pulmonary fibrosis. However, little is known about the incidence and seriousness of post–COVID-19 pulmonary pathology. Objectives: To describe the respiratory recovery and self-reported health after infection at the time of outpatient attendance. Methods: Infection severity was graded into three groups: 1 ) not requiring admission, 2 ) requiring hospital admission, and 3 ) requiring intensive care unit care. Participants underwent chest radiography and a 6-minute walk test (6MWT). Fatigue and subjective return to health were assessed, and concentrations of CRP (C-reactive protein), IL-6 (interleukin-6), sCD25 (soluble CD25), and D-dimer were measured. The associations between initial illness and abnormal chest X-ray findings, 6MWT distance, and perception of maximal exertion were investigated. Results: A total of 487 patients were offered an outpatient appointment, of whom 153 (31%) attended for assessment at a median of 75 days after diagnosis. A total of 74 (48%) had required hospital admission during acute infection. Persistently abnormal chest X-ray findings were seen in 4%. The median 6MWT distance covered was 460 m. A reduced distance covered was associated with frailty and length of inpatient stay. A total of 95 (62%) patients believed that they had not returned to full health, whereas 47% met the case definition for fatigue. Ongoing ill health and fatigue were associated with an increased perception of exertion. None of the measures of persistent respiratory disease were associated with initial disease severity. Conclusions: This study highlights the rates of objective respiratory disease and subjective respiratory symptoms after COVID-19 and the complex multifactorial nature of post–COVID-19 ill health.

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