Severe fatigue as symptom of long COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T-lymphocytes. A putative dysregulation of the immune-brain axis, the coagulation process, and auto-inflammation to explain the diversity of long COVID symptoms (preprint)

Background. A significant proportion of patients with SARS-CoV-2 infection develops long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immunologic profiling of fatigued and non-fatigued long COVID patients and age and gender matched healthy controls (HCs). Methods. We included 37 long COVID patients with and 36 without severe fatigue and assessed inflammation-related monocyte gene expression, serum levels of inflammatory cytokines, and leukocyte and lymphocyte subsets 3-6 months after hospital discharge, and followed clinical symptoms up to one year. Results. Long COVID with fatigue represented a severe variant with many symptoms (median 9 [IQR 5.0-10.0] symptoms) and signs of cognitive failure (41%) and depression (>24%). Symptoms persisted up to one year follow-up. Fatigued patients showed increased expression of inflammatory genes in monocytes, increased serum IL-6, TNF-, galectin-9, and CXCL10, and increased CD8+ T-lymphocytes compared to HCs. Non-fatigued long COVID patients were arbitrarily divided in those with moderately severe disease (4 [2.5-5.0] symptoms, primarily impaired fitness, n=25) and those with mild disease (1 [1.0-2.0] symptom, n=11). Symptoms in non-fatigued long COVID patients persisted up to one year follow-up. Moderately severe patients showed reduced CD45RO- naive CD4+ T-lymphocytes and CD25+FOXP3+ regulatory CD4+ T-lymphocytes and limited monocyte and serum (galectin-9) inflammation. Mild patients showed monocyte and serum (IL-6, galectin-9) inflammation and decreased CD4+ T-lymphocyte subsets (T-helper 1 cells). Conclusion. Long COVID with fatigue is associated with many concurrent and persistent symptoms up to one year after hospitalization and with clear signs of low grade inflammation and increased CD8+ T-lymphocytes. We showed that long COVID is a clinical and immunologic heterogeneous disorder. Diagnostic tools and personalized therapies combatting the diverse immune abnormalities might be required to alleviate the persisting disabling complaints of the patients.

Symptoms persisting after hospitalization for COVID-19: 12 months interim results of the COFLOW study (preprint)

Introduction: A large proportion of patients experiences a wide range of sequelae after acute COVID-19 infection, especially after severe illness. The long-term health sequelae need to be assessed. Our objective was to longitudinally assess persistence of symptoms and clusters of symptoms up to 12 months after hospitalization for COVID-19, and to assess determinants of the main persistent symptoms. Methods: In this multicenter prospective cohort study patients with COVID-19 are followed up for 2 years with measurements at 3, 6, 12, and 24 months after hospital discharge. Here, we present interim results regarding persistent symptoms up to 12 months. Symptoms were clustered into physical, respiratory, cognitive and fatigue symptoms. Results: We included 492 patients; mean age was 60.2 years, 335 (68.1%) males, median length of hospital stay 11 days. At 3 months after discharge 97.0% of the patients had at least 1 persisting symptom, this declined to 95.5% and 92.0% at 6 and 12 months, respectively (p=0.010). Muscle weakness, exertional dyspnea, fatigue, and memory and concentration problems were the most prevalent symptoms with rates over 50% during follow-up. Over time, muscle weakness, hair loss, and exertional dyspnea decreased significantly (p<0.001), while other symptoms, such as fatigue, concentration and memory problems, anosmia, and ageusia persisted. Symptoms from the physical and respiratory cluster declined significantly over time, in contrast to symptoms from the fatigue and cognitive clusters. Female gender was the most important predictor of persistent symptoms and co-occurrence of symptoms from all clusters. Shorter hospital stay and treatment with steroids were related with decreased muscle weakness; comorbidity and being employed were related with increased fatigue; and shorter hospital stay and comorbidity were related with memory problems. Conclusion: The majority of patients experienced COVID-19 sequelae up to 12 months after hospitalization. Whereas physical and respiratory symptoms showed slow gradual decline, fatigue and cognitive symptoms did not evidently resolve over time. This finding stresses the importance of finding the underlying causes and effective treatments for post-COVID condition, beside adequate COVID-19 prevention.