CLUSTER ANALYSIS IDENTIFIES LONG COVID SUBTYPES IN BELGIAN PATIENTS (preprint)

SARS CoV-2 infection presents complications known as long Covid, a multisystemic organ disease which allow multidimensional analysis. ObjectivesThis study aims to identify Long Covid clusters and to relate them to the clinical classification devised at the Clinical Research Unit of Brugmann University Hospital, Brussels. MethodA two-stage multidimensional exploratory analysis was performed on a cohort of 205 long Covid patients, involving a Factorial Analysis of Mixed Data (FAMD), and then Hierarchical Clustering Post Component Analysis (HCPC). ResultsThe studys sample comprised 76% women, with an average age of 44.5 years. Three clinical forms were identified: long, persistent, and post-viral syndrome. Multidimensional analysis identified three clusters: cluster 1 (myalgia-like pain) associated with the persistent clinical form; cluster 2 (neurocognitive disorders) linked to the long clinical form; cluster 3 (neurocognitive disorders, anxio-depressive syndrome, joint pain and myalgia, peripheral nervous system disorders with dysautonomia, including Postural Orthostatic Tachycardia Syndrome, along with digestive system disorders). However, biological data did not provide sufficient differentiation between the clusters. ConclusionLong Covid phenotypes, as well as clinical forms, appear to be associated with distinct pathophysiological mechanisms or genetic predisposition, warranting further investigation.

The comparison of the consultation-liaison in the psychiatry department of a general hospital before and after the outbreak of COVID-19 (preprint)

Objective: To compare the status of the consultation-liaison in the psychiatry department of inpatients in a general hospital before and after the outbreak of COVID-19.  Methods: 842 patients in a tertiary hospital during 2019 and 904 patients since the beginning of the epidemic in 2020 were enrolled in this study. Demographic data, departments that requested consultation, mental disorders, and the psychiatric treatments were retrospectively analyzed.  Results: Among the 1746 patients, most patients were 45 to 70 years old. The department of hematology received the most applications for consultation. In 2020, requests from the departments of cardiac and vascular surgeries, contrary to the emergency department, increased significantly. 32.6% patients were diagnosed with organic mental disorder. Delirium was the most common disorder, followed by anxiety and depression. After the COVID-19 outbreak in 2020, the stress-associated and sleep disorders increased.  Conclusions: In general hospitals, clinical departments have great demands forpsychiatric consultation.Since the pandemic, patients requiring consultations for stress-related disorders and sleep disorders increased. Moreover, patients with cardiac and major vascular surgeries suffering from mental and emotional disturbances also increased. The ability of non-psychiatrists in identifying and treating mental disorders and the awareness of biopsychosocial (BPS) models need to be improved.

COVID-19 and neurocognitive disorders.

PURPOSE OF REVIEW: The COVID-19 infection results in various viral-related physical and mental health problems, joined with the long-term psychological impact of the pandemic in general. However, the accompanying neurocognitive changes remain poorly understood. RECENT FINDINGS: We synthetize the current knowledge of viral (SARS-CoV-2) induced inflammation, mechanisms to viral entry into the central nervous system and altered neurotransmitter systems to provide an informed neurobiological explanation for the rise of neurocognitive disorders (defined as per the DSM-5 criteria). SUMMARY: The mild and major neurocognitive disorder symptoms due to the COVID-19 pandemic provide a unique opportunity to address the early changes underlying neurocognitive impairment at both clinical and molecular level. We discuss the utilization of the available evidence for their management and future novel therapeutic opportunities.

Researching COVID to enhance recovery (RECOVER) autopsy study protocol: Rationale, objectives, and design (preprint)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Tissue Pathology Study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. Methods: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Casual inference methods will be employed to investigate associations between risk factors and pathologic outcomes. Discussion: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

AHUS mistaken for TTP associated with COVID-19: a case report (preprint)

Thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) are both thrombotic microangiopathies that share several clinical traits including microangiopathic hemolytic anemia, thrombocytopenia, and organic damage. There is inherent opportunity for misdiagnosis. As thrombocytopenia and thrombus are strongly related to COVID-19, it may be more difficult to tell an aHUS from a TTP when COVID-19 is present. Thus, we describe a patient presenting with severe COVID-19 who was misdiagnosed with TTP but in the end corrected to aHUS. We suggest that perform detection to ADAMTS-13 activity and complement gene mutation as soon as possible is necessary.

[Postcovid cognitive impairment]. / Postkovidnye kognitivnye narusheniya.

This review addresses current issues in post-COVID syndrome with a focus on neurocognitive impairment. The results of studies on complications in patients of different ages and health statuses recovered from mild to severe COVID-19 are discussed. Current data on the pathogenetic mechanisms of the development of various post-COVID disorders are presented, including a detailed discussion of central nervous system damage. The paper summarizes data on the relationship between neurocognitive disorders and accelerated cell aging, chronic nonspecific inflammation, and reduced neuroplasticity in the central nervous system. The main pathogenetic ways to prevent COVID-related complications, including neuronal tissue damage and the prospects for managing such patients are discussed. The choice of pathogenetic therapy in patients with neurocognitive impairment in the post-COVID period is assessed. The main benefits of choline alfoscerate therapy for neurocognitive impairment in patients with post-COVID syndrome are discussed.

Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19 (preprint)

Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19, thus defining an anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.

Psychophysiologic symptom relief therapy (PSRT) for post-acute sequelae of COVID-19: a non-randomized interventional study (preprint)

Objective: To determine if psychophysiologic symptom relief therapy (PSRT) will reduce symptom burden in patients suffering from post-acute sequelae of COVID-19 (PASC) who had mild/moderate acute COVID-19 disease without objective evidence of organ injury. Patients and Methods: Twenty-three adults under the age of 60 with PASC for at least 12 weeks following COVID-19 infection were enrolled in an interventional cohort study conducted via virtual platform between May 18, 2021 and August 7, 2022. Participants received PSRT during a 13 week (approximately 44 hour) course. Participants were administered validated questionnaires at baseline and at 4, 8, and 13 weeks. The primary outcome was change in somatic symptoms from baseline, measured using the Somatic Symptom Scale-8 (SSS-8). Results: The median duration of symptoms prior to joining the study was 267 days (IQR: 144, 460). The mean SSS-8 score of the cohort decreased from baseline by 8.5 (95% CI: 5.7-11.4), 9.4 (95% CI: 6.9-11.9), and 10.9 (95% CI: 8.3-13.5) at 4, 8, and 13 weeks respectively (all p<0.001). Participants also experienced statistically significant improvements across secondary outcomes including changes in dyspnea, fatigue, and pain (all p<0.001). Conclusion: PSRT may effectively decrease symptom burden in patients suffering from PASC without evidence of organ injury. The study was registered on clinicaltrials.gov (NCT 04854772).

Clinical and Imaging Determinants of Neurocognitive Disorders in Post-Acute COVID-19 Patients with Cognitive Complaints.

BACKGROUND: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants. OBJECTIVE: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants. METHODS: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance. RESULTS: Repeated ANOVA showed a group effect (p = 0.0001) due to overall lower performance for patients and a domain effect (p = 0.0001) due to a lower (p = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2 = 0.319, p = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus. CONCLUSION: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern.

Cognitive, Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with Neurocognitive Disorders.

BACKGROUND: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions. OBJECTIVE: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders. METHODS: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018-May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020-May 2021) during the second wave of COVID-19. Neuropsychological tests were performed at baseline and six months after baseline. RESULTS: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p = 0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p = 0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p = 0.229) and Geriatric Depression Scale (GDS; p = 0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group. CONCLUSION: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences.

HMGB1 correlates with severity and death of COVID-19 patients (preprint)

SARS-CoV-2, the causative agent of the ongoing COVID-19, has spread worldwide since it was first identified in November 2019 in Wuhan. Since then, it was already demonstrated an exuberant inflammation, cytokine storm, endothelium dysfunction, platelets hyperactivation and aggregation, following T cell exhaustion leading to severe multi-organ damage and death of COVID-19 patients. Here, we sought to identify molecular biomarkers of disease severity in a Brazilian cohort of COVID-19 patients by measuring the serum levels of endogenous danger signals. Our data revealed that ICU patients that are critically ill, at the early hyperinflammatory phase of COVID-19 (around 12-25 days after hospital admission) display higher serum levels of the classical alarmin HMGB1. Serum levels of HMGB1 were positively correlated with cys-leukotrienes, D-dimer, AST, and ALT. Notably, we verified that HMGB1 levels above 125.4 ng/mL is the cut off that distinguishes the patients that are at higher risk of death. Serum levels of extracellular ATP, PGE<2, LTB4, cys-LTs, and tissue factor were also elevated in the serum of ICU patients. In conclusion, we propose that serum levels of HMGB1 serve as prognostic biomarker of risk of death in patients suffering from severe COVID-19.

Targeting Neutrophils Extracellular Traps (NETs) reduces multiple organ injury in a COVID-19 mouse model (preprint)

COVID-19 is characterized by severe acute lung injury, which is associated with neutrophils infiltration and release of neutrophil extracellular traps (NETs). COVID-19 treatment options are scarce. Previous work has shown an increase in NETs release in the lung and plasma of COVID-19 patients suggesting that drugs that prevent NETs formation or release could be potential therapeutic approaches for COVID-19 treatment. Here, we report the efficacy of NET-degrading DNase I treatment in a murine model of COVID-19. DNase I decreased detectable levels of NETs, improved clinical disease, and reduced lung, heart, and kidney injuries in SARS-CoV-2-infected K18-hACE2 mice. Furthermore, our findings indicate a potential deleterious role for NETs lung tissue in vivo and lung epithelial (A549) cells in vitro, which might explain part of the pathophysiology of severe COVID-19. This deleterious effect was diminished by the treatment with DNase I. Together, our results support the role of NETs in COVID-19 immunopathology and highlight NETs disruption pharmacological approaches as a potential strategy to ameliorate COVID-19 clinical outcomes.

The effect of the COVID-19 lockdown on mental health care use in South Africa: an interrupted time series analysis (preprint)

AimsIn March 2020, South Africa introduced a lockdown in response to the COVID-19 pandemic, entailing the suspension of all non-essential activities and a complete ban of tobacco and alcohol sales. We studied the effect of the lockdown on mental health care utilisation rates in private-sector care in South Africa. MethodsWe did an interrupted time series analysis using insurance claims from January 1, 2017, to June 1, 2020 of beneficiaries 18 years or older from a large private sector medical aid scheme. We calculated weekly outpatient consultation and hospital admission rates for organic mental disorders, substance use disorders, serious mental disorders, depression, anxiety, other mental disorders, any mental disorder, and alcohol withdrawal syndrome. We calculated adjusted odds ratios (OR) for the effect of the lockdown on weekly outpatient consultation and hospital admission rates and the weekly change in rates during the lockdown until June 1, 2020. Results710,367 persons were followed up for a median of 153 weeks. Hospital admission rates (OR 0.38; 95% CI 0.33-0.44) and outpatient consultation rates (OR 0.74; 95% CI 0.63-0.87) for any mental disorder decreased substantially after the lockdown and did not recover to pre-lockdown levels until June 1, 2020. Health care utilisation rates for alcohol withdrawal syndrome doubled after the introduction of the lockdown, but the statistical uncertainty around the estimates was large (OR 2.24; 95% CI 0.69-7.24). ConclusionsReduced mental health care contact rates during the COVID-19 lockdown likely reflect a substantial unmet need for mental health services with potential long-term consequences for mental health patients and their families. Steps to ensure access and continuity of mental health services during future lockdowns should be considered.

Mechanical Ventilation for Older Patients in Internal Medicine Units (preprint)

Purpose: The development of technologies for the prolongation of life has resulted in an increase in the number of older ventilated patients in internal medicine and chronic care wards. Our study aimed to determine the factors influencing the outcomes of older ventilated patients in internal medicine wards. Methods: We performed a prospective observational cohort study including all newly ventilated medical patients aged 65 years and older over a period of 18 months. Data were acquired from computerized medical records and from an interview of the medical personnel initiating mechanical ventilation. Results: A total of 554 underwent mechanical ventilation for the first time during the study period. The average age was 79 years, and 80% resided at home. Following mechanical ventilation, 8% died in the emergency room, and the majority of patients (351; 63%) were hospitalized in internal medicine wards. In-hospital mortality was 64.1%, with 48% dying during the first week of hospitalization. Overall 6-month survival was 26%. We found that a combination of age 85 years and older, functional status prior to ventilation, and associated morbidity (diabetes with target organ injury and / or oncological solid organ disease) were the strongest negative predictors of survival after discharge from the hospital. Conclusion: Mechanical ventilation at older age is associated with poor survival and it is possible to identify factors predicting survival. In the midst of the Covid-19 pandemic, the findings of this study may help in the decision-making process regarding mechanical ventilation for older people.

Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study (preprint)

Importance: Multi-organ impairment associated with Long COVID is a significant burden to individuals, populations and health systems, presenting challenges for diagnosis and care provision. Standardised assessment across multiple organs over time is lacking, particularly in non-hospitalised individuals. Objective: To determine the prevalence of organ impairment in Long COVID patients at 6 and at 12 months after initial symptoms and to explore links to clinical presentation. Design: This was a prospective, longitudinal study in individuals following recovery from acute COVID-19. We assessed symptoms, health status, and multi-organ tissue characterisation and function, using consensus definitions for single and multi-organ impairment. Physiological and biochemical investigations were performed at baseline on all individuals and those with organ impairment were reassessed, including multi-organ MRI, 6 months later. Setting: Two non-acute settings (Oxford and London). Participants: 536 individuals (mean 45 years, 73% female, 89% white, 32% healthcare workers, 13% acute COVID-19 hospitalisation) completed baseline assessment (median: 6 months post-COVID-19). 331 (62%) with organ impairment or incidental findings had follow up, with reduced symptom burden from baseline (median number of symptoms: 10 and 3, at 6 and 12 months). Exposure: SARS-CoV-2 infection 6 months prior to first assessment. Main outcome: Prevalence of single and multi-organ impairment at 6 and 12 months post-COVID-19. Results: Extreme breathlessness (36% and 30%), cognitive dysfunction (50% and 38%) and poor health-related quality of life (EQ-5D-5L<0.7; 55% and 45%) were common at 6 and 12 months, and associated with female gender, younger age and single organ impairment. At baseline, there was fibro-inflammation in the heart (9%), pancreas (9%), kidney (15%) and liver (11%); increased volume in liver (7%), spleen (8%) and kidney (9%); decreased capacity in lungs (2%); and excessive fat deposition in the liver (25%) and pancreas (15%). Single and multi-organ impairment were present in 59% and 23% at baseline, persisting in 59% and 27% at follow-up. Conclusion and Relevance: Organ impairment was present in 59% of individuals at 6 months post-COVID-19, persisting in 59% of those followed up at 1 year, with implications for symptoms, quality of life and longer-term health, signalling need for prevention and integrated care of Long COVID. Trial Registration: ClinicalTrials.gov NCT04369807

Neurocognitive Rehabilitation in COVID-19 Patients: A Clinical Review.

Abstract: COVID-19 has affected many people all around the world for more than two years now have suffered many long-term consequences which is commonly referred to as long-haulers. Despite multiorgan complaints in long haulers, symptoms related to cognitive functions commonly referred as brain fog are seen in the high risk covid patients with age more than 50, women more than men, obesity, asthma and those who experienced more than five symptoms during the first week of covid illness. Long term isolation has certainly contributed to high level of anxiety and stress calling for an empathetic response to this group of covid patients as there is no specific test to detect long haulers and no specific cognitive rehabilitation techniques available as of today.