A novel methodology for the synchronous collection and multimodal visualisation of continuous neurocardiovascular and neuromuscular physiological data in adults with long COVID (preprint)

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. To accomplish such an investigation, a wide range of continuous non-invasive biomedical 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. With the novel technique described and exemplified in this paper, we were able to integrate signals from all instruments used in the assessment in a precisely synchronized fashion. We demonstrate that it is possible to visualize the interactions between all 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. The proposed multimodal data visualization can offer an overview of the functioning of the muscle pump during both supine rest and orthostatic recovery and can conduct comparison studies with signals from multiple participants at any given time in the assessment. This could help researchers and clinicians generate and test hypotheses based on the multimodal inspection of raw data, in long COVID and other clinical cohorts.

Orthostatic intolerance in adults with long COVID was not associated with postural orthostatic tachycardia syndrome (preprint)

In this observational cross-sectional study, we investigated predictors of orthostatic intolerance (OI) in adults with long COVID. Participants underwent a 3-minute active stand (AS) with Finapres® NOVA, followed by a 10-minute unmedicated 70-degree head-up tilt test. 85 participants were included (mean age 46 years, range 25-78; 74% women), of which 56 (66%) reported OI during AS (OI AS ). OI AS 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 1 st minute post-stand (mean HR nadir 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, HR nadir was the only OI AS predictor (OR=1.09, 95% CI: 1.01-1.18, P=0.027). 22 participants had initial (iOH) and 5 classical (cOH) orthostatic hypotension, but neither correlated with OI AS . 71 participants proceeded to tilt, of which 28 had OI during tilt (OI tilt ). Of the 53 who had a 10-minute tilt, 7 (13%) fulfilled hemodynamic postural orthostatic tachycardia syndrome (POTS) criteria, but 6 did not report OI tilt . OI AS was associated with a higher initial HR on AS, which after 1 minute equalized with the non-OI AS group. Despite these initial orthostatic HR differences, POTS was infrequent and largely asymptomatic. ClinicalTrials.gov Identifier: NCT05027724 (retrospectively registered on August 30, 2021).

A systematic review of persistent symptoms and residual abnormal functioning following acute COVID-19: Ongoing symptomatic phase vs. post-COVID-19 syndrome (preprint)

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 1,145 studies screened, 39 were included, all describing adult cohorts with long COVID and sample sizes ranging from 32 to 1,733. 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 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% of patients with OSC and 57% by those with PCS. Conclusions | The prevalences of OSC and PCS were highly variable. Reported symptoms covered a wide range of body systems, with 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 better understand the complex interplay of somatic versus psychosocial drivers in long COVID. Systematic Review Registration | Registered with PROSPERO with ID #CRD42021247846.

Renin-angiotensin system inhibitors and severity of SARS-CoV-2 infection: a meta-analysis (preprint)

Introduction The mechanism of entry of SARS-CoV-2 into the human host cell is through the ACE2 receptor. During the pandemic, a hypothesis has been proposed that Angiotensin-converting enzyme inhibitors (ACEi) and Angiotensin II receptor blockers (ARBs) could be risk factors for the development of severe SARS-CoV-2 infection. Objective To conduct a meta-analysis of the association between ACEi or ARB use and SARS-CoV-2 infection severity or mortality.Data Sources We searched PubMed, EMBASE, Google scholar and the Cochrane Database of Systematic Reviews for observational studies published between December 2019 and April 24, 2020Study Selection: Studies were included if they contained data on ACEi or ARB use and SARS-CoV-2 infection severity or mortality. Effect statistics were pooled using random-effects models. The quality of included studies was assessed with the Newcastle–Ottawa Scale (NOS). Data ExtractionData on study design, study location, year of publication, study design, number of participants, sex, age at baseline, outcome definition, exposure definition, follow-up, effect estimates and 95% Cis.Results Thirteen observational studies were identified for inclusion, combining to a total sample of 14364 participants. Mean age was 59.2 (SD 7.3) years and 53.5% were men. Mean follow-up was 28.3 (14.2) days. The mean NOS score of included studies was 7.8 (range: 7-9). Results suggested that ACEi or ARB use did not increase the risk of severe disease or mortality from SARS-CoV-2 infection (OR=0.72, 95% CI 0.47-1.11, p= 0.138).ConclusionsAt present, the limited evidence available does not support the hypothesis of increased SARS-CoV-2 risk with ACEi or ARB drugs. However, more evidence needs to accumulate before this controversy can be resolved.