Greater Role of Cognitive Impairment Over Fatigue in Post-COVID-19 Quality of Life: A Post-Hoc Analysis of a Randomized Controlled Trial (preprint)

BackgroundPost COVID-19 Condition (PCC) is a common and debilitating condition with significant reports of fatigue and psychosocial impairment globally. The extent to which cognitive symptoms and fatigue contribute to reduced quality of life in affected individuals remains clear. MethodsThis is a post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial that evaluated the effect of vortioxetine on cognitive function in adults with PCC. The post-hoc analysis herein aimed to determine the overall effect of baseline cognitive function [as measured by the Digit Symbol Substitution Test (DSST)] and baseline fatigue severity [as measured by the Fatigue Severity Scale (FSS)] on baseline health-related quality of life (HRQoL) [as measured by the 5-item World Health Organisation Well-Being Index (WHO-5)]. ResultsA total of 200 participants were enrolled in the primary trial. Due to missing baseline data, our statistical analysis included baseline measures of 147 individuals. Our generalized linear model analysis revealed a significant positive correlation between DSST-measured objective cognitive function and self-reported WHO-5-measured HRQoL ({beta} = 0.069, 95% CI [0.006, 0.131], p = 0.032). In contrast, our analysis revealed a significant negative correlation between FSS and WHO-5 scores ({beta} = -0.016, 95% CI [-0.021, -0.011], p < 0.001). The beta-coefficient ratio ({beta}DSST / {beta}FSS = 0.069 / 0.016) is calculated as 4.313. ConclusionsOverall, we observed that increased cognitive function was associated with increased HRQoL at baseline in adults with PCC. Moreover, we observed that increased severity of fatigue symptoms was associated with decreased HRQoL at baseline in adults with PCC. Furthermore, we observed that an improvement in cognitive function would have a four-fold greater impact on HRQoL than the effect generated by improvement in fatigue.

Subjective and Objective Measures of Cognitive Function are Correlated in Persons with Post-COVID-19 Condition: A Secondary Analysis of a Randomized Controlled Trial (preprint)

Background: It remains unclear whether subjective and objective measures of cognitive function in Post COVID-19 Condition (PCC) are correlated. The extent of correlation has mechanistic and clinical implications. Methods This post-hoc analysis of a randomized, double-blind, placebo-controlled clinical trial contains baseline data of subjective and objective measures of cognition in a rigorously characterized cohort living with PCC. Herein, we evaluated the association between subjective and objective condition function, as measured by the Perceived Deficits Questionnaire, 20-item (PDQ-20) and the Digit Symbol Substitution Test (DSST) and Trails Making Test (TMT)-A/B, respectively. Results A total of 152 participants comprised the baseline sample. Due to missing data, our statistical analyses included 150 for self-reported PDQ-20, 147 individuals for combined DSST-measured cognitive function (composite z-score of the Pen/Paper plus Online CogState Version, NcombinedDSST), 71 for in-person DSST-measured cognitive function (Pen/Paper Version), 70 for TMT-A-measured cognitive function, and 70 for TMT-B-measured cognitive function. After adjusting for age, sex, and education, PDQ-20 was significantly correlated with pen-and-paper DSST (β = -0.003, p = 0.002) and TMT-B (β = 0.003, p = 0.008) scores, but not with TMT-A scores (β = -0.001, p = 0.751). Conclusions Overall, a statistically significant correlation was observed between subjective and objective cognitive functions. Clinicians providing care for individuals with PCC who have subjective cognitive function complaints may consider taking a measurement-based approach to cognition at the point of care that focuses exclusively on patient-reported measures.

The Impact of Cognitive Function on Health-Related Quality of Life in Persons with Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine (preprint)

Background Post-Covid-19 Condition (PCC) manifests in persistent, debilitating symptoms that affect multiple cognitive domains. These symptoms can negatively impact an affected individual's health-related quality of life (HRQoL). Herein, we investigate the effects of cognitive function on HRQoL in persons with PCC. Secondarily, we determine whether vortioxetine modulates cognitive function on HRQoL. Methods Participants aged 18-65 years were randomized to receive vortioxetine or placebo for 8 weeks. HRQoL was measured using the World Health organization Wellbeing Scale 5-item, cognition was measured using the Digit Symbol Substitution Test and the Trail-Making Test A/B. Generalized estimating equations were used to model the relationship of cognition to HRQoL for each treatment group. Results 147 participants, 75.5% of which were female, were included in the analysis. At baseline, there was a statistically significant positive association between WHO-5 scores and combined DSST z-scores (beta; = 0.090, 95% CI [0.051, 0.129], p < 0.001), and a statistically significant negative association with TMT-A (beta; = -0.007, 95% CI [-0.011, -0.003], p < 0.001) and -B (beta; = -0.002, 95% CI [-0.003, 0.000], p = 0.024) scores, respectively. A significant treatment, time, and combined DSST z-score interaction on changes in overall WHO-5 total score (x2 = 15.481, p = 0.004) was reported. After adjusting for the type of cognitive test, there was a significant between-group difference (mean change = 1.77, SEM = 0.868, p = 0.042) favoring vortioxetine. Conclusion Cognitive function is significantly associated with HRQoL in persons with PCC where enhanced cognitive functioning is associated with a better HRQoL. Vortioxetine is effective in improving HRQoL through enhancing cognitive function. Cognitive function in persons with PCC provides the impetus for future therapeutic targets for persons with PCC. Future studies should aim to investigate pro-cognitive therapeutic strategies.

Association of SARS-CoV-2 Infection with Neurological Symptoms and Neuroimaging Manifestations in the Pediatric Population: A Systematic Review (preprint)

Background Neurological manifestations have been widely reported in adults with COVID-19, yet the extent of involvement among the pediatric population is currently poorly characterized. The objective of our systematic review is to evaluate the association of SARS-CoV-2 infection with neurological symptoms and neuroimaging manifestations in the pediatric population.Methods A literature search of Cochrane Library; EBSCO CINAHL; Global Index Medicus; OVID AMED, Embase, Medline, PsychINFO; and Scopus was conducted in accordance with the Peer Review of Electronic Search Strategies form (October 1, 2019 to March 15, 2022). Studies were included if they reported (1) COVID-19-associated neurological symptoms and neuroimaging manifestations in individuals aged < 18 years with a confirmed, first SARS-CoV-2 infection and were (2) peer-reviewed. Full-text reviews of 222 retrieved articles were performed, along with subsequent reference searches.Results A total of 843 nonduplicate records were retrieved. Of the 19 identified studies, there were ten retrospective observational studies, seven case series, one case report, and one prospective cohort study. A total of 6,985 individuals were included, where 12.8% of hospitalized patients experienced neurocognitive impairments: MIS-C (24.2%), neuroinflammation (10.1%), and encephalopathy (8.1%) were the most common disorders; headaches (16.8%) and seizures (3.8%) were the most common symptoms. Based on pediatric-specific cohorts, children experienced more drowsiness (7.3% vs. 1.3%) and muscle weakness (7.3% vs. 6.3%) as opposed to adolescents. Agitation or irritability was observed more in children (7.3%) than infants (1.3%).Conclusion Our findings revealed a high prevalence of immune-mediated patterns of disease among COVID-19 positive pediatric patients with neurocognitive abnormalities.