Hepatic disorders associated with the use of Ivermectin for SARS-CoV-2 infection in adults: a pharmacovigilance study in VigiBase

Aim: The aim of the present study was to review in VigiBase the reports of serious hepatic disorders associated with the use of ivermectin for COVID-19 in adults. Background: In the face of the global health emergency caused by SARS-CoV-2, ivermectin, among other drugs, has been repurposed in some Latin American countries to treat COVID-19. Studies are needed on the safety of ivermectin for this new indication. VigiBase is the WHO pharmacovigilance database that registers all individual case safety reports (ICSRs) from more than 130 countries. Methods: We extracted the ICSRs of men or women aged ≥ 18 years and dated between 1 January 2020 and 7 March 2021 which included an association with the use of ivermectin. Results: Of 1393 ICSRs associated with ivermectin, 60 (4.3%) were registered as "serious." Ivermectin had been used for COVID-19 in 25 of those cases. Among the latter, 6 experienced hepatic disorders (hepatitis, hepatocellular injury, cholestasis, increased alanine aminotransferase and/or aspartate aminotransferase levels, abnormal liver function tests). Conclusion: The safety of the use of ivermectin should be studied more exhaustively, especially as regards the possibility of hepatic disorders developing when the drug is used for COVID-19.

Being a frail older person at a time of the COVID-19 pandemic

During the COVID-19 pandemic, older people living with frailty were identified as vulnerable to poor health outcomes. While writing this chapter in December 2020, we reviewed early evidence on what it meant to be a frail older individual in the COVID-19 pandemic from the perspective of three different settings: community, hospitals, and nursing homes. Lessons learned provide opportunities to improve health outcomes, community and health services, and how we want to live as aging societies.

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.

Study protocol for the St James's Hospital, Tallaght University Hospital, Trinity College Dublin Allied Researchers' (STTAR) Bioresource for COVID-19.

Background: The current coronavirus disease 2019 (COVID-19) pandemic began in Ireland with the first confirmed positive case in March 2020. In the early stages of the pandemic clinicians and researchers in two affiliated Dublin hospitals identified the need for a COVID-19 biobanking initiative to support and enhance research into the disease. Through large scale analysis of clinical, regional, and genetic characteristics of COVID-19 patients, biobanks have helped identify, and so protect, at risk patient groups The STTAR Bioresource has been created to collect and store data and linked biological samples from patients with SARS-CoV-2 infection and healthy and disease controls. Aim: The primary objective of this study is to build a biobank, to understand the clinical characteristics and natural history of COVID-19 infection with the long-term goal of research into improved disease understanding, diagnostic tests and treatments. Methods: This is a prospective dual-site cohort study across two tertiary acute university teaching hospitals. Patients are recruited from inpatient wards or outpatient clinics. Patients with confirmed COVID-19 infection as well as healthy and specific disease control groups are recruited.  Biological samples are collected and a case report form detailing demographic and medical background is entered into the bespoke secure online Dendrite database. Impact: The results of this study will be used to inform national and international strategy on health service provision and disease management related to COVID-19. In common with other biobanks, study end points  evolve over time as new research questions emerge. They currently include patient survival, occurrence of severe complications of the disease or its therapy, occurrence of persistent symptoms following recovery from the acute illness and vaccine responses.

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 mixed-methods feasibility study of a sit-to-stand based exercise programme to maintain knee-extension muscle strength for older patients during hospitalisation.

OBJECTIVES: To determine the acceptability of an exercise programme and to identify barriers and facilitators to compliance with the programme from the participants' perspective. METHODS: Patients aged 75 years or older were recruited within the first 36 hours of hospital admission. Participants were randomised to complete two strengthening-based (intervention arm) or stretching-based (control arm) exercise sessions per-day. At hospital discharge, participants were asked to take part in interviews with a member of the research team exploring the barriers and facilitators to adherence to the intervention. RESULTS: 15 participants (7 intervention arm, 8 control arm) were recruited before the trial was stopped due to COVID-19. Both groups showed reductions in knee-extension strength, and improvements in functional mobility at discharge from hospital. A total of 23/60 intervention sessions were classed as 'complete', 12/60 as partially complete, and 25/60 were missed entirely. Eight participants took part in interviews. Intrinsic factors that impacted participation in the research, related to current health, health beliefs, and experience of multi-morbidity or functional decline. Staff had both a positive and negative effect on participant adherence to the intervention. CONCLUSIONS: The exercise intervention was well received, with most participants describing health benefits, though intervention fidelity was lower than expected.

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.

Being a frail older person at the time of the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, frail older individuals have been identified as a particularly vulnerable group for poor health outcomes, including cognitive decline and dementia. We aimed to reflect on the interaction between frailty and COVID-19 with regards to health consequences. METHOD: Using a rapid literature review approach, we aimed to identify what it means to be a frail older individual in the COVID-19 pandemic from the perspective of three different settings: community, hospitals, and nursing homes. Four researchers from 4 countries (Ireland, France, Germany, and Brazil) reviewed articles from the MEDLINE database and grey literature including public policy briefs from their countries. RESULTS: In the community, some governments advised to practice "cocooning", i.e. stay-at-home-orders for older individuals. This brought unprecedented restrictions to lifestyles, leading to a potential frailty cascade among older adults. Social frailty likely caused mental ill-health, cognitive and functional decline, increasing the risk for dementia. In hospitals, frailty affected from disease onset to survivorship. The clinical presentation was rather atypical, and the biological findings were more heterogenous. Some resource allocation strategies based on the Clinical Frailty Scale remained questionable and should take into account patients' and carers' needs. A quarter of patients had increased care needs at discharge. However, availability of rehabilitation and support services in the community has been reduced. Frail older adults living in nursing homes were the most vulnerable group. Isolating residents and limiting the spread of COVID-19 was a key difficulty. Reduced visits from relatives, cancelled physical activities, and lack of social engagement worsened cognitive, behavioral, and physical conditions of the residents. There were also positive aspects such as the boom of digital literacy and telemedicine and a renewed debate on age and ageing. CONCLUSIONS: The COVID-19 pandemic spotlights the ageing population that is rapidly growing worldwide. Prolonged lifestyle restrictions during the pandemic led to poor health outcomes in frail older individuals, including cognitive decline and dementia. Lessons learned from how frail older individuals are getting through the pandemic provide a unique chance to improve health outcomes, community and health services and how we want to live as ageing societies.

Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis.

Introduction Hydroxychloroquine (HCQ) has been proposed as a SARS-CoV-2 treatment but the frequency of long QT (LQT) during use is unknown. Objective To conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ. Data Sources PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) were searched for studies published between December 2019 and June 30, 2020. Methods Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively. Outcomes Critical LQT was defined as: (1) maximum QT corrected (QTc)≥500 ms (if QRS<120 ms) or QTc≥550 ms (if QRS≥120 ms), and (2) QTc increase ≥60 ms. Results In the 28 studies included (n=9124), the frequency of LQT during HCQ treatment was 6.7% (95% confidence interval [CI]: 3.7-10.2). In 20 studies (n=7825), patients were also taking other QT-prolonging drugs. The frequency of LQT in the other 8 studies (n=1299) was 1.7% (95% CI: 0.3-3.9). Twenty studies (n=6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-6.6). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death was 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). Patients aged >60 years were at highest risk of HCQ-associated LQT (P<0.001). Conclusions HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring, particularly in those aged >60 years and/or taking other QT-prolonging drugs.

Involving older people in co-designing an intervention to reverse frailty and build resilience.

BACKGROUND: An essential consideration in health research is to conduct research with members of the public rather than for them. Public and patient involvement (PPI) of older people in research can improve enrolment, relevance and impact. However, few studies with PPI in frailty research have been identified. PPI has fallen during the Covid-19 pandemic. OBJECTIVE: We aimed to involve older people in co-designing a randomised control trial (RCT) intervention to reverse frailty and build resilience. We also wished to encourage wider use of PPI with older people by outlining our approach. METHODS: Involvement of older people was undertaken in three stages. Eighteen over 65-year-olds helped co-design an exercise intervention in two group discussions using the Socratic education method. Ninety-four contributed intervention feedback in one-on-one telephone interviews over nine months. Ten contributors helped optimise the intervention in three online workshops. Multidisciplinary team input and systematic review supported co-design. RESULTS: Eleven home-based resistance exercises were co-designed by group discussion contributors (mean age 75, 61% female). Frailty intervention format, gender balance and GP follow-up were shaped in telephone interviews (mean age 77, 63% female). Dietary guidance and patient communication were co-designed in workshops (mean age 71, 60% females). Technology proved no barrier to PPI. The co-designed frailty intervention is being evaluated in a definitive RCT. CONCLUSIONS: We enabled meaningful the involvement of 112 older people in the co-design of an intervention to reverse frailty and build resilience in diverse ways. Inclusive involvement can be achieved during a pandemic. Feedback enhanced intervention feasibility for real-world primary-care.

Our research paper describes how we involved 112 older adults in the co-design of an intervention aiming to reverse frailty and build resilience. Involving participants in research can improve its feasibility and impact. However, there have been few studies involving older people in frailty research and involvement has fallen further during the Covid-19 pandemic. Involvement of older people was undertaken in three stages. Eighteen over 65-year-olds helped co-design an exercise intervention in two group discussions. Ninety-four older adults contributed intervention feedback in one-on-one telephone interviews over nine months. Ten contributors helped optimise the intervention in three online workshops. The co-designed intervention involved resistance exercises and dietary guidance and will be tested in a full randomised control trial. We enabled the meaningful involvement of 112 older people in our research in diverse ways. Inclusive involvement can be achieved during a pandemic.

The relationship between the severity and mortality of SARS-CoV-2 infection and 25-hydroxyvitamin D concentration - a metaanalysis.

INTRODUCTION: There is increasing scientific interest in the possible association between hypovitaminosis D and the risk of SARS-CoV-2 infection severity and/or mortality. OBJECTIVE: To conduct a metanalysis of the association between 25-hydroxyvitamin D (25(OH)D) concentration and SARS-CoV-2 infection severity or mortality. MATERIAL AND METHODS: We searched PubMed, EMBASE, Google scholar and the Cochrane Database of Systematic Reviews for studies published between December 2019 and December 2020. Effect statistics were pooled using random effects models. The quality of included studies was assessed with the Newcastle-Ottawa Scale (NOS). Targeted outcomes: mortality and severity proportions in COVID-19 patients with 25(OH)D deficiency, defined as serum 25(OH)D < 50 nmol/L. RESULTS: In the 23 studies included (n = 2692), the mean age was 60.8 (SD ± 15.9) years and 53.8% were men. Results suggested that vitamin 25(OH)D deficiency was associated with increased risk of severe SARS-CoV-2 disease (RR 2.00; 95% CI 1.47-2.71, 17 studies) and mortality (RR 2.45; 95% CI 1.24-4.84, 13 studies). Only 7/23 studies reported C-reactive protein values, all of which were > 10 mg/L. Conclusions 25(OH)D deficiency seems associated with increased SARS-CoV-2 infection severity and mortality. However, findings do not imply causality, and randomized controlled trials are required, and new studies should be designed to determine if decreased 25(OH)D is an epiphenomenon or consequence of the inflammatory process associated with severe forms of SARS-CoV-2. Meanwhile, the concentration of 25(OH)D could be considered as a negative acute phase reactant and a poor prognosis in COVID-19 infection.

A pharmacological perspective of chloroquine in SARS-CoV-2 infection: An old drug for the fight against a new coronavirus?

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having serious consequences on health and the economy worldwide. All evidence-based treatment strategies need to be considered to combat this new virus. Drugs need to be considered on scientific grounds of efficacy, safety and cost. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used in the treatment of malaria. Moreover, their antiviral properties have been previously studied, including against coronaviruses, where evidence of efficacy has been found. In the current race against time triggered by the COVID-19 pandemic, the search for new antivirals is very important. However, consideration should be given to old drugs with known anti-coronavirus activity, such as CQ and HCQ. These could be integrated into current treatment strategies while novel treatments are awaited, also in light of the fact that they display an anticoagulant effect that facilitates the activity of low-molecular-weight heparin, aimed at preventing acute respiratory distress syndrome (ARDS)-associated thrombotic events. The safety of CQ and HCQ has been studied for over 50 years, however recently published data raise concerns for cardiac toxicity of CQ/HCQ in patients with COVID-19. This review also re-examines the real information provided by some of the published alarming reports, although concluding that cardiac toxicity should in any case be stringently monitored in patients receiving CQ/HCQ.