Comprehensive Clinical Characterisation of Brain Fog in Adults Reporting Long COVID Symptoms.

(1) Introduction: A subset of individuals experiencing long COVID symptoms are affected by 'brain fog', a lay term that often refers to general cognitive dysfunction but one that is still poorly characterised. In this study, a comprehensive clinical characterisation of self-reported brain fog was conducted vis-à-vis other long COVID symptoms and parameters of mental, cognitive, and physical health. (2) Methodology: Adult participants reporting long COVID symptoms were recruited from hospital clinics and as self-referrals. Participants completed a battery of questionnaires and clinical assessments, including COVID-19 history, symptomatology, self-reported scales (Chalder Fatigue Scale [CFQ], Center for Epidemiological Studies Depression Scale, and Impact of Events Scale-Revised), computer-based cognitive assessments (simple response time and choice reaction time tasks), physical performance tests (gait velocity and muscle strength assessments), and an orthostatic active stand test. A systematic comparison between participants with and without self-reported brain fog was conducted, and a backwards binary logistic regression model was computed to identify the strongest independent associations with brain fog. This was complemented by an automatic cluster analysis to rank the importance of associations. Finally, a structural equation model was postulated with a causal model of key symptomatic indicators and functional consequences of brain fog as a latent variable. (3) Results: Of 108 participants assessed, brain fog was a self-reported symptom in 71 (65.7%) participants. Those with brain fog were at a longer point in time since COVID-19 onset and reported longer duration of low activity during the acute illness. When assessed, those with brain fog had higher frequencies of subjective memory impairment, word-finding difficulties, dizziness, myalgia, arthralgia, hyperhidrosis, cough, voice weakness, throat pain, visual and hearing problems, dysosmia, paraesthesia, chest pain, skin rashes, and hair loss; mean scores in fatigue, depression, and post-traumatic stress scales were higher; performance in both computer-based cognitive tasks was poorer; and measured gait speed and grip strength were lower. The logistic regression suggested that the best independent associations with brain fog were memory impairment, CFQ, and myalgia. The cluster analysis suggested that the most important associations with brain fog were CFQ, dizziness, myalgia, reduced gait speed, word-finding difficulties, reduced grip strength, and memory impairment. The SEM was consistent with key indicators of brain fog being CFQ, dizziness, myalgia, word-finding difficulties, and memory impairment; and reduced grip strength, gait speed, and cognitive response times its functional consequences. (4) Conclusions: The findings indicate that self-reported brain fog in long COVID is a recognisable symptom cluster primarily characterised by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment and has adverse psychological and psychomotor correlates. In long COVID, brain fog should be regarded as a wide-ranging symptom and addressed holistically with medical, psychological, and rehabilitative supports as guided by individual needs.

Predictors of Submaximal Exercise Test Attainment in Adults Reporting Long COVID Symptoms.

Adults with long COVID often report intolerance to exercise. Cardiopulmonary exercise testing (CPET) has been used in many settings to measure exercise ability but has been conducted in a few long COVID cohorts. We conducted CPET in a sample of adults reporting long COVID symptoms using a submaximal cycle ergometer protocol. We studied pre-exercise predictors of achieving 85% of the age-predicted maximum heart rate (85%HRmax) using logistic regression. Eighty participants were included (mean age 46 years, range 25-78, 71% women). Forty participants (50%) did not reach 85%HRmax. On average, non-achievers reached 84% of their predicted 85%HRmax. No adverse events occurred. Participants who did not achieve 85%HRmax were older (p < 0.001), had more recent COVID-19 illness (p = 0.012) with higher frequency of hospitalization (p = 0.025), and had been more affected by dizziness (p = 0.041) and joint pain (p = 0.028). In the logistic regression model including age, body mass index, time since COVID-19, COVID-19-related hospitalization, dizziness, joint pain, pre-existing cardiopulmonary disease, and use of beta blockers, independent predictors of achieving 85%HRmax were younger age (p = 0.001) and longer time since COVID-19 (p = 0.008). Our cross-sectional findings suggest that exercise tolerance in adults with long COVID has potential to improve over time. Longitudinal research should assess the extent to which this may occur and its mechanisms. ClinicalTrials.gov identifier: NCT05027724 (TROPIC Study).

Orthostatic Intolerance in Adults Reporting Long COVID Symptoms Was Not Associated With Postural Orthostatic Tachycardia Syndrome.

In this observational cross-sectional study, we investigated predictors of orthostatic intolerance (OI) in adults reporting long COVID symptoms. Participants underwent a 3-min active stand (AS) with Finapres® NOVA, followed by a 10-min unmedicated 70° head-up tilt test. Eighty-five participants were included (mean age 46 years, range 25-78; 74% women), of which 56 (66%) reported OI during AS (OIAS). OIAS seemed associated with female sex, more fatigue and depressive symptoms, and greater inability to perform activities of daily living (ADL), as well as a higher heart rate (HR) at the lowest systolic blood pressure (SBP) point before the first minute post-stand (mean HRnadir: 88 vs. 75 bpm, P = 0.004). In a regression model also including age, sex, fatigue, depression, ADL inability, and peak HR after the nadir SBP, HRnadir was the only OIAS predictor (OR = 1.09, 95% CI: 1.01-1.18, P = 0.027). Twenty-two (26%) participants had initial (iOH) and 5 (6%) classical (cOHAS) orthostatic hypotension, but neither correlated with OIAS. Seventy-one participants proceeded to tilt, of which 28 (39%) had OI during tilt (OItilt). Of the 53 who had a 10-min tilt, 7 (13%) had an HR increase >30 bpm without cOHtilt (2 to HR > 120 bpm), but six did not report OItilt. In conclusion, OIAS was associated with a higher initial HR on AS, which after 1 min equalised with the non-OIAS group. Despite these initial orthostatic HR differences, POTS was infrequent (2%). ClinicalTrials.gov Identifier: NCT05027724 (retrospectively registered on August 30, 2021).

A Novel Methodology for the Synchronous Collection and Multimodal Visualization of Continuous Neurocardiovascular and Neuromuscular Physiological Data in Adults with Long COVID.

Background: Reports suggest that adults with post-COVID-19 syndrome or long COVID may be affected by orthostatic intolerance syndromes, with autonomic nervous system dysfunction as a possible causal factor of neurocardiovascular instability (NCVI). Long COVID can also manifest as prolonged fatigue, which may be linked to neuromuscular function impairment (NMFI). The current clinical assessment for NCVI monitors neurocardiovascular performance upon the application of orthostatic stressors such as an active (i.e., self-induced) stand or a passive (tilt table) standing test. Lower limb muscle contractions may be important in orthostatic recovery via the skeletal muscle pump. In this study, adults with long COVID were assessed with a protocol that, in addition to the standard NCVI tests, incorporated simultaneous lower limb muscle monitoring for NMFI assessment. Methods: To conduct such an investigation, a wide range of continuous non-invasive biomedical sensing technologies were employed, including digital artery photoplethysmography for the extraction of cardiovascular signals, near-infrared spectroscopy for the extraction of regional tissue oxygenation in brain and muscle, and electromyography for assessment of timed muscle contractions in the lower limbs. Results: With the proposed methodology described and exemplified in this paper, we were able to collect relevant physiological data for the assessment of neurocardiovascular and neuromuscular functioning. We were also able to integrate signals from a variety of instruments in a synchronized fashion and visualize the interactions between different physiological signals during the combined NCVI/NMFI assessment. Multiple counts of evidence were collected, which can capture the dynamics between skeletal muscle contractions and neurocardiovascular responses. Conclusions: The proposed methodology can offer an overview of the functioning of the neurocardiovascular and neuromuscular systems in a combined NCVI/NMFI setup and is capable of conducting comparative studies with signals from multiple participants at any given time in the assessment. This could help clinicians and researchers generate and test hypotheses based on the multimodal inspection of raw data in long COVID and other cohorts.

A Systematic Review of Persistent Symptoms and Residual Abnormal Functioning following Acute COVID-19: Ongoing Symptomatic Phase vs. Post-COVID-19 Syndrome.

OBJECTIVE: To compare the two phases of long COVID, namely ongoing symptomatic COVID-19 (OSC; signs and symptoms from 4 to 12 weeks from initial infection) and post-COVID-19 syndrome (PCS; signs and symptoms beyond 12 weeks) with respect to symptomatology, abnormal functioning, psychological burden, and quality of life. DESIGN: Systematic review. DATA SOURCES: Electronic search of EMBASE, MEDLINE, ProQuest Coronavirus Research Database, LitCOVID, and Google Scholar between January and April 2021, and manual search for relevant citations from review articles. Eligibility Criteria: Cross-sectional studies, cohort studies, randomised control trials, and case-control studies with participant data concerning long COVID symptomatology or abnormal functioning. DATA EXTRACTION: Studies were screened and assessed for risk of bias by two independent reviewers, with conflicts resolved with a third reviewer. The AXIS tool was utilised to appraise the quality of the evidence. Data were extracted and collated using a data extraction tool in Microsoft Excel. RESULTS: Of the 1145 studies screened, 39 were included, all describing adult cohorts with long COVID and sample sizes ranging from 32 to 1733. Studies included data pertaining to symptomatology, pulmonary functioning, chest imaging, cognitive functioning, psychological disorder, and/or quality of life. Fatigue presented as the most prevalent symptom during both OSC and PCS at 43% and 44%, respectively. Sleep disorder (36%; 33%), dyspnoea (31%; 40%), and cough (26%; 22%) followed in prevalence. Abnormal spirometry (FEV1 < 80% predicted) was observed in 15% and 11%, and abnormal chest imaging was observed in 34% and 28%, respectively. Cognitive impairments were also evident (20%; 15%), as well as anxiety (28%; 34%) and depression (25%; 32%). Decreased quality of life was reported by 40% in those with OSC and 57% with PCS. CONCLUSIONS: The prevalence of OSC and PCS were highly variable. Reported symptoms covered a wide range of body systems, with a general overlap in frequencies between the two phases. However, abnormalities in lung function and imaging seemed to be more common in OSC, whilst anxiety, depression, and poor quality of life seemed more frequent in PCS. In general, the quality of the evidence was moderate and further research is needed to understand longitudinal symptomatology trajectories in long COVID. Systematic Review Registration: Registered with PROSPERO with ID #CRD42021247846.