Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19.

OBJECTIVE AND DESIGN: Fatigue is a prominent symptom in the general population and may follow viral infection, including SARS-CoV2 infection which causes COVID-19. Chronic fatigue lasting more than three months is the major symptom of the post-COVID syndrome (known colloquially as long-COVID). The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of long-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual prior to COVID-19. SUBJECTS AND METHODS: We analyzed pre-pandemic plasma levels of IL-6, which plays a key role in persistent fatigue, in N = 1274 community dwelling adults from TwinsUK. Subsequent COVID-19-positive and -negative participants were categorized based on SARS-CoV-2 antigen and antibody testing. Chronic fatigue was assessed using the Chalder Fatigue Scale. RESULTS: COVID-19-positive participants exhibited mild disease. Chronic fatigue was a prevalent symptom among this population and significantly higher in positive vs. negative participants (17% vs 11%, respectively; p = 0.001). The qualitative nature of chronic fatigue as determined by individual questionnaire responses was similar in positive and negative participants. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in negative, but not positive individuals. Raised BMI was associated with chronic fatigue in positive participants. CONCLUSIONS: Pre-existing increased IL-6 levels may contribute to chronic fatigue symptoms, but there was no increased risk in individuals with mild COVID-19 compared with uninfected individuals. Elevated BMI also increased the risk of chronic fatigue in mild COVID-19, consistent with previous reports.

Neurogenesis is disrupted in human hippocampal progenitor cells upon exposure to serum samples from hospitalized COVID-19 patients with neurological symptoms.

Coronavirus disease 2019 (COVID-19), represents an enormous new threat to our healthcare system and particularly to the health of older adults. Although the respiratory symptoms of COVID-19 are well recognized, the neurological manifestations, and their underlying cellular and molecular mechanisms, have not been extensively studied yet. Our study is the first one to test the direct effect of serum from hospitalised COVID-19 patients on human hippocampal neurogenesis using a unique in vitro experimental assay with human hippocampal progenitor cells (HPC0A07/03 C). We identify the different molecular pathways activated by serum from COVID-19 patients with and without neurological symptoms (i.e., delirium), and their effects on neuronal proliferation, neurogenesis, and apoptosis. We collected serum sample twice, at time of hospital admission and approximately 5 days after hospitalization. We found that treatment with serum samples from COVID-19 patients with delirium (n = 18) decreased cell proliferation and neurogenesis, and increases apoptosis, when compared with serum samples of sex- and age-matched COVID-19 patients without delirium (n = 18). This effect was due to a higher concentration of interleukin 6 (IL6) in serum samples of patients with delirium (mean ± SD: 229.9 ± 79.1 pg/ml, vs. 32.5 ± 9.5 pg/ml in patients without delirium). Indeed, treatment of cells with an antibody against IL6 prevented the decreased cell proliferation and neurogenesis and the increased apoptosis. Moreover, increased concentration of IL6 in serum samples from delirium patients stimulated the hippocampal cells to produce IL12 and IL13, and treatment with an antibody against IL12 or IL13 also prevented the decreased cell proliferation and neurogenesis, and the increased apoptosis. Interestingly, treatment with the compounds commonly administered to acute COVID-19 patients (the Janus kinase inhibitors, baricitinib, ruxolitinib and tofacitinib) were able to restore normal cell viability, proliferation and neurogenesis by targeting the effects of IL12 and IL13. Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.

Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis.

BACKGROUND: Mental disorders might be a risk factor for severe COVID-19. We aimed to assess the specific risks of COVID-19-related mortality, hospitalisation, and intensive care unit (ICU) admission associated with any pre-existing mental disorder, and specific diagnostic categories of mental disorders, and exposure to psychopharmacological drug classes. METHODS: In this systematic review and meta-analysis, we searched Web of Science, Cochrane, PubMed, and PsycINFO databases between Jan 1, 2020, and March 5, 2021, for original studies reporting data on COVID-19 outcomes in patients with psychiatric disorders compared with controls. We excluded studies with overlapping samples, studies that were not peer-reviewed, and studies written in languages other than English, Danish, Dutch, French, German, Italian, and Portuguese. We modelled random-effects meta-analyses to estimate crude odds ratios (OR) for mortality after SARS-CoV-2 infection as the primary outcome, and hospitalisation and ICU admission as secondary outcomes. We calculated adjusted ORs for available data. Heterogeneity was assessed using the I2 statistic, and publication bias was tested with Egger regression and visual inspection of funnel plots. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle Ottawa Scale to assess study quality. We also did subgroup analyses and meta-regressions to assess the effects of baseline COVID-19 treatment setting, patient age, country, pandemic phase, quality assessment score, sample sizes, and adjustment for confounders. This study is registered with PROSPERO, CRD42021233984. FINDINGS: 841 studies were identified by the systematic search, of which 33 studies were included in the systematic review and 23 studies in the meta-analysis, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. The sample included 130 807 females (8·9% of the whole sample) and 130 373 males (8·8%). Nine studies provided data on patient race and ethnicity, and 22 studies were rated as high quality. The presence of any mental disorder was associated with an increased risk of COVID-19 mortality (OR 2·00 [95% CI 1·58-2·54]; I2=92·66%). This association was also observed for psychotic disorders (2·05 [1·37-3·06]; I2=80·81%), mood disorders (1·99 [1·46-2·71]; I2=68·32%), substance use disorders (1·76 [1·27-2·44]; I2=47·90%), and intellectual disabilities and developmental disorders (1·73 [1·29-2·31]; I2=90·15%) but not for anxiety disorders (1·07 [0·73-1·56]; I2=11·05%). COVID-19 mortality was associated with exposure to antipsychotics (3·71 [1·74-7·91]; I2=90·31%), anxiolytics (2·58 [1·22-5·44]; I2=96·42%), and antidepressants (2·23 [1·06-4·71]; I2=95·45%). For psychotic disorders, mood disorders, antipsychotics, and anxiolytics, the association remained significant after adjustment for age, sex, and other confounders. Mental disorders were associated with increased risk of hospitalisation (2·24 [1·70-2·94]; I2=88·80%). No significant associations with mortality were identified for ICU admission. Subgroup analyses and meta-regressions showed significant associations of baseline COVID-19 treatment setting (p=0·013) and country (p<0·0001) with mortality. No significant associations with mortality were identified for other covariates. No evidence of publication bias was found. GRADE assessment indicated high certainty for crude mortality and hospitalisation, and moderate certainty for crude ICU admission. INTERPRETATION: Pre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiolytics were associated with COVID-19 mortality in both crude and adjusted models. Although further research is required to determine the underlying mechanisms, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in at-risk patient groups identified in this study. FUNDING: None. TRANSLATIONS: For the Italian, French and Portuguese translations of the abstract see Supplementary Materials section.