Prognostic value of SOFA combined with chest CT severity score in patients with critical COVID-19 pneumonia: a retrospective study (preprint)

Background: Either sequential organ failure assessment (SOFA) score or chest CT severity score (CT-SS) is often used alone to evaluate the prognosis of patients with critical coronavirus disease 2019 (COVID-19), but each of them has intrinsic deficiency. Herein, we attempted to investigate the predictive value of the combination of SOFA and CT-SS for the prognosis of COVID-19. Materials and Methods: A single-center retrospective study was performed in the Second Affiliated Hospital of Zhejiang University School of Medicine from December 2022 to January 2023. Patients with critical COVID-19 pneumonia were divided into two groups of survival or non-survival of hospitalization. The data including clinical characteristics, CT-SS, SOFA score, laboratory results on admission day were collected and analyzed. In addition, the predictive value of SOFAscore, chest CT-SS, or their combination for in-hospital mortality of COVID-19 pneumonia were compared by receiver operating characteristic (ROC) curve. Results: A total of 424 patients with a mean age of 75.46 years and a major proportion of male (69.10%) were finally enrolled, and the total in-hospital mortality was 43.40% (184/424). In comparison with survival group, significant higher proportions of older age (>75 years), comorbidities including obesity, diabetes, and cerebrovascular disease, more needs of mechanical ventilation and continuous renal replacement therapy (CRRT) were observed in the non-survival group (all P﹤0.05). In addition, non-survival patients had a higher value of creatinine, procalcitonin, C-reactive protein, interleukin-6 , SOFA score , CT-SS  (all P﹤0.05) on admission day. Multivariate logistic regression analysis further showed that older age, obesity, diabetes, SOFA score, CT-SS, mechanical ventilation, and lymphocytopenia (all P﹤0.05) were independently related with in-hospital mortality. Moreover, the area under the curve (AUC) of combination of SOFA score and chest CT-SS became significant higher than their respective alone (P＜0.01). Conclusion: A simple combination of SOFA scorewith chest CT-SS on admission elicits a better predictive value for in-hospital mortality of critical COVID-19 patients, which could also serve as a promising indicator for prognosis prediction of other severe lung diseases like severe pneumonia and acute lung injury.

Severity and Mortality in Maintenance Hemodialysis Patients Infected with COVID-19 Omicron Strain: a Single-Centered, Retrospective Study in China (preprint)

Purpose The aim of this study was to observe the characteristics of COVID-19 infected maintenance hemodialysis (MHD) patients, identify the risk factors for severe illness and mortality in this population, and establish a preliminary risk prediction model for severe COVID-19 infection of MHD patients.Methods We included patients who underwent long-term maintenance hemodialysis and were hospitalized for COVID-19 infection at our hospital from December 2022 to March 2023. We retrospectively analyzed their demographic characteristics, clinical manifestations, laboratory tests, hemodialysis-related information, treatment strategies and complications. The patients were divided into severe (heavy and critical) and non-severe (mild and moderate) groups. Logistic regression and Cox proportional hazards analysis were used to identify the risk factors for severe COVID-19 progression.Results The presence of cerebrovascular disease, elevated NLR, fibrinogen, and D-dimer are independent risk indicators for severe COVID-19 infection in MHD patients in early stage. The presence of diabetes, cerebrovascular disease, and elevated D-dimer and NLR were associated with mortality.Conclusion MHD patients have a high probability of developing into severe and critical COVID-19 infection, and NLR, fibrinogen, and D-dimer can serve as early warning indicators for severe and critical progression of COVID-19 infection. The presence of diabetes, cerebrovascular disease, elevated NLR and D-dimer levels attribute to worse clinical outcomes and increased mortality.

Clinical characteristics and analysis of risk factors for disease progression in patients on maintenance hemodialysis infected with SARS-CoV-2 omicron variant (preprint)

Objective:To summarize the clinical characteristics of patients on maintenance hemodialysis (MHD) with the novel coronavirus omicron variant and explore the risk factors for severe cases. Methods:We retrospectively analyzed the data of 158 patients on MHD from Zhongnan Hospital of Wuhan University between December 7, 2022 and January 31, 2023. We collected clinical data, described clinical characteristics, and analyzed the relationships between these factors and critical illness using univariate and multivariate logistic regression analyses. Results: The median age of the 158 patients was 63 (interquartile range: 52–71) years, and 128 (63.7%) were men. Fever (62.7%) and cough (60.1%) were the two most common symptoms. Hypertension (80.4%) was the most common comorbidity, followed by diabetes (31.0%), cardiovascular disease (22.8%), and cerebrovascular disease (15.2%). Unvaccinated patients constituted the majority of the enrolled patients (88.6%, 140/158), whereas only a small proportion (11.4%, 18/158) had been vaccinated (including fully vaccinated and partially vaccinated patients). Multivariate logistic regression analysis indicated that an elevated C-reactive protein (CRP) level (odds ratio [OR]: 1.03, 95% confidence interval [CI], 1.014–1.046], p<0.001) and a decreased platelet count (OR: 0.986, 95% CI, 0.986 (0.976–0.997), p=0.013) during hospitalization were risk factors for the severe group. Conclusions:This study demonstrated a high mortality rate among patients on MHD infected with omicron variant. Furthermore, advanced age, increased CRP levels, and decreased platelet count were predictors of critical illness.

Multimorbidity characteristics in elderly inpatients and their associated factors in complex networks: a cross-sectional study (preprint)

Background Multimorbidity of chronic diseases has become an increasingly serious public health problem. However, the research on the current situation of multimorbidity in the elderly in Jiangsu, China is relatively lacking. Methods We surveyed a total of 229,926 inpatients aged above 60 and with two or more chronic diseases in the First Affiliated Hospital with Nanjing Medical University from January 1, 2015 to December 31, 2021. The Apriori algorithm was used to analyze the association rules of the multimorbidity patternsin old adults. Results The mean age of these patients was 72.0±8.7 years, and the male-to-female ratio was 1:1.53. These patients during the COVID-19 period(from 2020 to 2021) displayed younger, higher male rate, shorter median length of hospital stay, higher ≥6 multimorbidities rate and lower median cost than those not during the COVID-19 period (from 2015 to 2019). In all of these patients, the top 5 chronic diseases were "Hypertensive diseases(I10-I15)", "Other forms of heart disease(I30-I52)", "Diabetes mellitus(E10-E14)", "lschaemic heart diseases(I20-I25)" and "Cerebrovascular diseases(I60-I69)". The complex networks of multimorbidity showed that Hypertensive diseases had a higher probability of co-occurrence with multiple diseases in all these patients, followed by Diabetes mellitus, Other forms of heart disease, and lschaemic heart diseases(I20-I25). Conclusion In conclusion, the patterns of multimorbidity among the aged varied by COVID-19. Our results highlighted the importance of control of hypertensive diseases, diabetes, and heart disease in gerontal patients. More efforts to improve the understanding of multimorbidity patterns would help us develop new clinical and family care models.

Epigenetic liquid biopsies reveal elevated vascular endothelial cell turnover and erythropoiesis in asymptomatic COVID-19 patients (preprint)

The full spectrum of tissues affected by SARS-CoV-2 infection is crucial for deciphering the heterogenous clinical course of COVID-19. Here, we analyzed DNA methylation and histone modification patterns in circulating chromatin to assess cell type-specific turnover in severe and asymptomatic COVID-19 patients, in relation to clinical outcome. Patients with severe COVID-19 had a massive elevation of circulating cell-free DNA (cfDNA) levels, which originated in lung epithelial cells, cardiomyocytes, vascular endothelial cells and erythroblasts, suggesting increased cell death or turnover in these tissues. The immune response to infection was reflected by elevated B cell and monocyte/macrophage cfDNA levels, and by evidence of an interferon response in cells prior to cfDNA release. Strikingly, monocyte/macrophage cfDNA levels (but not monocyte counts), as well as lung epithelium cfDNA and vascular endothelial cfDNA, predicted clinical deterioration and duration of hospitalization. Asymptomatic patients had elevated levels of immune-derived cfDNA but did not show evidence of pulmonary or cardiac damage. Surprisingly, these patients showed elevated levels of vascular endothelial cell and erythroblast cfDNA, suggesting that sub-clinical vascular and erythrocyte turnover are universal features of COVID-19, independent of disease severity. Epigenetic liquid biopsies provide non-invasive means of monitoring COVID-19 patients, and reveal sub-clinical vascular damage and red blood cell turnover.

Cerebrovascular Disease in COVID-19 (preprint)

Not in the history of transmissible illnesses has there been an infection as strongly associated with acute cerebrovascular disease as the novel human coronavirus, SARS-CoV-2. While the risk of stroke has known associations with other viral infections, such as influenza and human immunodeficiency virus, the risk of ischemic and hemorrhagic stroke related to SARS-CoV-2 is unprecedented. Furthermore, the coronavirus disease 2019 (COVID-19) pandemic has so profoundly impacted psychosocial behaviors and modern medical care that we have witnessed shifts in epidemiology and have adapted our treatment practices to reduce transmission, address delayed diagnoses, and mitigate gaps in health care. In this narrative review, we summarize the history and impact of the COVID-19 pandemic on cerebrovascular disease, and lessons learned regarding the management of patients as we endure this period of human history.

COVID-19 and Cerebrovascular Disease.

COVID-19 has been associated with numerous neurological complications, with acute cerebrovascular disease being one of the most devastating complications. Ischemic stroke is the most common cerebrovascular complication of COVID-19, affecting between 1 and 6% of all patients. Underlying mechanisms for COVID-related ischemic strokes are thought to be due to vasculopathy, endotheliopathy, direct invasion of the arterial wall, and platelet activation. Other COVID-19-associated cerebrovascular complications include hemorrhagic stroke, cerebral microbleeds, posterior reversible encephalopathy syndrome, reversible cerebral vasoconstriction syndrome, cerebral venous sinus thrombosis, and subarachnoid hemorrhage. This article discusses the incidence of these cerebrovascular complications, risk factors, management strategies, prognosis and future research directions, as well as considerations in pregnancy-related cerebrovascular events in the setting of COVID-19.

Arterial stiffness measured by pulse wave velocity correlated with cognitive decline in hypertensive individuals: A systematic review (preprint)

Background Arterial stiffness is a degenerative modification of the arterial wall significantly influencing normal aging, longevity, and vascular health. Hypertension is a major risk factor for the development of arterial stiffness, which can lead to changes in cerebral perfusion and cognitive dysfunction. This, in turn, can increase the risk of cognitive decline. Pulse wave velocity (PWV) is an established gold standard for measuring arterial stiffness. Studies have shown that individuals with hypertension and elevated PWV are more likely to experience worse cognitive decline compared to those with either condition alone. The current literature, however, demonstrates controversial results. The aim of this article is to review the most recent published studies linking arterial stiffness to cognitive function in individuals with arterial hypertension. Methods We conducted a systematic review following the Cochrane protocol that was registered through the NIHR PROSPERO system. The PRISMA 2020 guidelines were used for reporting the systematic review. PubMed, Embase, Web of Science, CINAHL, and Cochrane databases were searched for relevant publications from early June to the end of December 2022. This review includes publications with a sample size of at least 500 participants older than 45 years. Screening of abstracts and full-text review of chosen articles were carried out through the Covidence. Results A total of 434 articles were selected for the full-text review. Twenty-four longitudinal studies and four cross-sectional designs that met the inclusion criteria were selected for the comparisons. The total sample size for these studies was 56,946 individuals. Twenty-seven studies (95%) demonstrated a significant association between arterial stiffness and cognitive dysfunction in hypertensive individuals. One study reported an association between stiffness and cognition independent of blood pressure (5% of the total population). Conclusion The results of this systematic review showed that arterial hypertension is one of the most important factors linking arterial stiffness to cognitive disorders. Pulse wave velocity was shown to be a strong measure associated with cognitive decline in aging individuals with chronically elevated blood pressure. Early screening for arterial stiffness, hypertension treatment, and effective prevention of cerebrovascular disease are imperative for cognitive health. NIHR PROSPERO registry ID: CRD 42022379887

History of cerebrovascular disease but not dementia increases the risk for secondary vascular events during SARS-CoV-2 infection with presumed Omicron variant: a retrospective observational study.

BACKGROUND AND PURPOSE: This study aimed to investigate if pre-existing neurological conditions, such as dementia and a history of cerebrovascular disease, increase the risk of severe outcomes including death, intensive care unit (ICU) admission and vascular events in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2022, when Omicron was the predominant variant. METHODS: A retrospective analysis was conducted of all patients with SARS-CoV-2 infection, confirmed by polymerase chain reaction test, admitted to the University Medical Center Hamburg-Eppendorf from 20 December 2021 until 15 August 2022. In all, 1249 patients were included in the study. In-hospital mortality was 3.8% and the ICU admission rate was 9.9%. Ninety-three patients with chronic cerebrovascular disease and 36 patients with pre-existing all-cause dementia were identified and propensity score matching by age, sex, comorbidities, vaccination status and dexamethasone treatment was performed in a 1:4 ratio with patients without the respective precondition using nearest neighbor matching. RESULTS: Analysis revealed that neither pre-existing cerebrovascular disease nor all-cause dementia increased mortality or the risk for ICU admission. All-cause dementia in the medical history also had no effect on vascular complications under investigation. In contrast, an increased odds ratio for both pulmonary artery embolism and secondary cerebrovascular events was observed in patients with pre-existing chronic cerebrovascular disease and myocardial infarction in the medical history. CONCLUSION: These findings suggest that patients with pre-existing cerebrovascular disease and myocardial infarction in their medical history may be particularly susceptible to vascular complications following SARS-CoV-2 infection with presumed Omicron variant.

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Neurological Manifestations in COVID-19 Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Growing evidence showed that coronavirus disease 2019 (COVID-19) infection may present with neurological manifestations. This review aimed to determine the neurological manifestations and complications in COVID-19. METHODS: We conducted a systematic review and meta-analysis that included cohort and case series/reports involving a population of patients confirmed with COVID-19 infection and their neurologic manifestations. We searched the following electronic databases until April 18, 2020: PubMed, Embase, Scopus, and World Health Organization database (PROSPERO registration number: CRD42020180658). RESULTS: From 403 articles identified, 49 studies involving a total of 6,335 confirmed COVID-19 cases were included. The random-effects modeling analysis for each neurological symptom showed the following proportional point estimates with 95% confidence intervals: "headache" (0.12; 0.10-0.14; I2 = 77%), "dizziness" (0.08; 0.05-0.12; I2 = 82%), "headache and dizziness" (0.09; 0.06-0.13; I2 = 0%), "nausea" (0.07; 0.04-0.11; I2 = 79%), "vomiting" (0.05; 0.03-0.08; I2 = 74%), "nausea and vomiting" (0.06; 0.03-0.11; I2 = 83%), "confusion" (0.05; 0.02-0.14; I2 = 86%), and "myalgia" (0.21; 0.18-0.25; I2 = 85%). The most common neurological complication associated with COVID-19 infection was vascular disorders (n = 23); other associated conditions were encephalopathy (n = 3), encephalitis (n = 1), oculomotor nerve palsy (n = 1), isolated sudden-onset anosmia (n = 1), Guillain-Barré syndrome (n = 1), and Miller-Fisher syndrome (n = 2). Most patients with neurological complications survived (n = 14); a considerable number of patients died (n = 7); and the rest had unclear outcomes (n = 12). CONCLUSION: This review revealed that neurologic involvement may manifest in COVID-19 infection. What has initially been thought of as a primarily respiratory illness has evolved into a wide-ranging multi-organ disease.

Coronavirus disease 2019 infection and cerebrovascular diseases: an update on the pathophysiology and management.

PURPOSE OF REVIEW: COVID-19 is an ongoing global pandemic since it was first discovered in 2020. Cerebral vascular disease and stroke are among the most common and devastating neurological manifestations of COVID-19. This review offers an up-to-date information on the possible underlying mechanism of COVID-19-related stroke, its diagnosis, and management. RECENT FINDINGS: The thromboembolism associated with COVID-19 infection is likely related to the cytokine storm with innate immune activation, pulmonary disease leading to hypoxia-induced ischemia, thrombotic microangiopathy, endothelial damage and multifactorial activation of the coagulation cascade. Currently, there is no clear guidelines on the use of antithrombotics for the prevention and treatment of this phenomenon. SUMMARY: COVID-19 infection can directly cause a stroke or facilitate the formation of thromboembolism in the presence of other medical conditions. Physicians treating patients with COVID-19 should stay vigilant about the signs and symptoms of stroke, detect and treat early.

Posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome in patients with COVID-19 infection: is there a link? A systematic review and case report analysis.

During the SARS-CoV2 pandemic, several cases of Posterior Reversible Encephalopathy Syndrome (PRES) and of Reversible Cerebral Vasoconstriction Syndrome (RCVS) in COVID-19 patients have been reported, but the link between these syndromes and COVID-19 is unclear. We performed a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to evaluate whether SARS-CoV2 infection or the drugs used to treat it could be deemed potential risk factors for PRES or RCVS. We performed a literature search. We found 70 articles (60 on PRES and 10 on RCVS) concerning n = 105 patients (n = 85 with PRES, n = 20 with RCVS). We analyzed the clinical characteristics of the two populations separately, then performed an inferential analysis to search for other independent risk factors. We found fewer than usual PRES-related (43.9%) and RCVS-related (45%) risk factors in patients with COVID-19. Such a low incidence of risk factors for PRES and RCVS might suggest the involvement of COVID-19 as an additional risk factor for both diseases due to its capability to cause endothelial dysfunction. We discuss the putative mechanisms of endothelial damage by SARS-CoV2 and antiviral drugs which may underlie the development of PRES and RCVS.

Temporal Trend in Mortality from COVID-19 Associated with Cardiovascular Disease (preprint)

Background: The COVID-19 pandemic has endured for over three years with over twelve variants afflicting humans worldwide. The impact and longevity of the pandemic has driven the medical community and researchers to identify high-risk populations, yet few studies have explored temporal trends during the pandemic. The objective of this study is to investigate trends in all-cause mortality associated with co-morbid cardiovascular disease (CVD) throughout the consecutive waves of the COVID-19 pandemic. Methods: A retrospective cohort study was conducted on patients with COVID-19 infection who received care at a tertiary care center in Chicago between March 2020 and September 2022. Multivariable logistic regression was used to investigate associations between co-existing CVD (defined as congestive heart failure, myocardial infarction, cerebrovascular disease, peripheral vascular disease) and mortality, adjusting for age, sex, race, and comorbidities defined in the Charlson comorbidity index. Results: The study included 38651 participants (mean age 45 years, 57.6% female, 11.4% with co-existing CVD). All-cause mortality in COVID-19 patients was highest during the Delta wave and remained elevated until the late Omicron wave. Mortality associated with co-existing CVD increased during the early pandemic waves, decreased in the later waves, but remained elevated relative to the overall population. When adjusted for age, sex, and race, all-cause mortality was 2.3-fold higher in patients with co-existing CVD compared to those with non-CVD comorbidities (OR = 2.30, 95% CI 1.95 - 2.62; p < 0.001). Conclusions: While overall mortality rates declined toward the later waves of the pandemic, all-cause mortality associated with CVD remained elevated compared to individuals without CVD.

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (preprint)

Neurological complications occur in a significant proportion of COVID-19 cases. In order to identify key biomarkers, we measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants admitted to hospital for management of COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided convalescent sera (up to76 weeks post admission). Compared to 60 controls, brain injury biomarkers (total-Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in participants with altered consciousness. Total-Tau (tTau) and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness and correlated with brain injury biomarker levels. Inflammatory mediators were lower in convalescent sera than acute sera. Levels of CCL2, CCL7, IL-1RA, IL-2Rα, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with tTau levels even at later time points. When compared to acute COVID-19 patients with a normal Glasgow Coma Scale score (GCS), network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFNγ, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase of COVID-19 and we found brain injury markers persist during convalescence and may be driven by a para-infectious process involving a dysregulated host response.

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (preprint)

We measured brain injury markers, inflammatory mediators, and autoantibodies in 203 participants with COVID-19; 111 provided acute sera (1-11 days post admission) and 56 with COVID-19-associated neurological diagnoses provided subacute/convalescent sera (6-76 weeks post-admission). Compared to 60 controls, brain injury biomarkers (Tau, GFAP, NfL, UCH-L1) were increased in acute sera, significantly more so for NfL and UCH-L1, in patients with altered consciousness. Tau and NfL remained elevated in convalescent sera, particularly following cerebrovascular and neuroinflammatory disorders. Acutely, inflammatory mediators (including IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) were higher in participants with altered consciousness, and correlated with brain injury biomarker levels. Inflammatory mediators were lower than acute levels in convalescent sera, but levels of CCL2, CCL7, IL-1RA, IL-2R, M-CSF, SCF, IL-16 and IL-18 in individual participants correlated with Tau levels even at this late time point. When compared to acute COVID-19 patients with a normal GCS, network analysis showed significantly altered immune responses in patients with acute alteration of consciousness, and in convalescent patients who had suffered an acute neurological complication. The frequency and range of autoantibodies did not associate with neurological disorders. However, autoantibodies against specific antigens were more frequent in patients with altered consciousness in the acute phase (including MYL7, UCH-L1, GRIN3B, and DDR2), and in patients with neurological complications in the convalescent phase (including MYL7, GNRHR, and HLA antigens). In a novel low-inoculum mouse model of SARS-CoV-2, while viral replication was only consistently seen in mouse lungs, inflammatory responses were seen in both brain and lungs, with significant increases in CCL4, IFN{gamma}, IL-17A, and microglial reactivity in the brain. Neurological injury is common in the acute phase and persists late after COVID-19, and may be driven by a para-infectious process involving a dysregulated host response.

Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs (preprint)

Factors of the innate immune response to SARS-CoV-2 in the lungs are pivotal for the ability of the host to deal with the infection. In humans, excessive macrophage infiltration is associated with disease severity. Using 3D spatiotemporal analysis of optically cleared hamster lung slices in combination with virological, immunohistochemical and RNA sequence analyses, we visualized the spread of SARS-CoV-2 through the lungs and the rapid anti-viral response in infected lung epithelial cells, followed by a wave of monocyte-derived macrophage (MDM) infiltration and virus elimination from the tissue. These SARS-CoV-2 induced innate immune processes are closely related to the onset of necrotizing inflammatory and consecutive remodelling responses in the lungs, which manifests as extensive cell death, vascular damage, thrombosis, and cell proliferation. Here we show that MDM are directly linked to virus clearance, and appear in connection with tissue injury and blood vessel damage. Rapid initiation of prothrombotic factor upregulation, tissue repair and alveolar cell proliferation results in tissue remodelling, which is followed by fibrosis development despite a decrease in inflammatory and anti-viral activities. Thus, although the hamsters are able to resolve the infection following the MDM influx and repair lung tissue integrity, longer-term alterations of the lung tissues arise as a result of concurrent tissue damage and regeneration processes.

Stuttering-Like Dysfluencies as a Consequence of Long COVID-19.

PURPOSE: We present two patients who developed neurogenic stuttering after long COVID-19 related to SARS-CoV-2 infection. METHODS AND RESULTS: Both patients experienced both physical (e.g., fatigue) and cognitive difficulties, which led to impaired function of attention, lexical retrieval, and memory consolidation. Both patients had new-onset stuttering-like speech dysfluencies: Blocks and repetitions were especially evident at the initial part of words and sentences, sometimes accompanied by effortful and associated movements (e.g., facial grimaces and oro-facial movements). Neuropsychological evaluations confirmed the presence of difficulties in cognitive tasks, while neurophysiological evaluations (i.e., electroencephalography) suggested the presence of "slowed" patterns of brain activity. Neurogenic stuttering and cognitive difficulties were evident for 4-5 months after negativization of SARS-CoV-2 nasopharyngeal swab, with gradual improvement and near-to-complete recovery. CONCLUSIONS: It is now evident that SARS-CoV-2 infection may significantly involve the central nervous system, also resulting in severe and long-term consequences, even if the precise mechanisms are still unknown. In the present report, long COVID-19 resulted in neurogenic stuttering, as the likely consequence of a "slowed" metabolism of (pre)frontal and sensorimotor brain regions (as suggested by the present and previous clinical evidence). As a consequence, the pathophysiological mechanisms related to the appearance of neurogenic stuttering have been hypothesized, which help to better understand the broader and possible neurological consequences of COVID-19.