Selina Greuel

Bio: Selina Greuel is an academic researcher from Humboldt University of Berlin. The author has contributed to research in topics: Interquartile range & Sepsis. The author has an hindex of 9, co-authored 16 publications receiving 513 citations. Previous affiliations of Selina Greuel include Charité.

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.

Abstract: The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.

Causes of death and comorbidities in hospitalized patients with COVID-19.

Abstract: Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has been associated with more than two million deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of pre-existing health conditions to death yet is missing, which can be reliably established by autopsy only. We performed full body autopsies on 26 patients that had died after SARS-CoV-2 infection and COVID-19 at the Charite University Hospital Berlin, Germany, or at associated teaching hospitals. We systematically evaluated causes of death and pre-existing health conditions. Additionally, clinical records and death certificates were evaluated. We report findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.

Association Between SARS-CoV-2 Infection and Immune-Mediated Myopathy in Patients Who Have Died.

Abstract: Importance Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3;P Conclusions and Relevance In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.

Standardization of Reporting Criteria for Lung Pathology in SARS-CoV-2 Infected Hamsters - What Matters?

Abstract: Respiratory failure because of severe lung pathology is the prime indication for emergency care and decisive for disease outcome in patients with coronavirus disease (COVID-19). Though clinical and computed tomography data are widely accessible, limited autopsy data are available where comorbidities may confound the spectrum of lesions (1, 2). However, a detailed understanding of viral spread, target cells and organs, time-dependent tissue damage, inflammatory responses, and regeneration and repair is essential for optimal clinical management and the development of preventive and therapeutic measures. In particular, disease mechanisms beyond classical pneumonia play a serious role in COVID-19, including vascular lesions (1, 3). For elucidation and the testing of drugs and vaccines, a suitable animal model is needed urgently. As mice are not naturally susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several transgenic models and viral vectors have been developed that express the human ACE2 receptor (4). However, the outcome of infections varied depending on modelspecific artificial expression levels and cellular distributions of the transgenic receptor, which still limits their interpretability. Besides less practical alternatives including primates (5–7), the Syrian hamster is emerging as a popular naturally susceptible small animal model. Importantly, first histopathology reports revealed several similarities to pulmonary changes observed in patients with COVID-19 (8–10). However, microscopic descriptions mentioned only select facets of the complex changes and used divergent nomenclatures, which makes comparisons and interpretations of the different studies difficult. Moreover, a systematic comparison to what is known of human COVID-19 pneumonia is lacking. Clearly, the reporting criteria for lung pathology patterns need to be harmonized with an agreement on what is relevant for humans before hamsters can be beneficial in preclinical studies. After all, among other functional, cellular and molecular, and more measurable parameters, histological evidence of tissue injury is viewed as the most relevant defining feature of acute lung injury by the American Thoracic Society (11). Standardized evaluation criteria for proven or potentially important diagnostic parameters are useful as guidelines for the harmonization, comparability, reproducibility, and robustness of diverse studies aiming at understanding disease mechanisms and testing vaccines or novel therapeutic strategies, and they are particularly useful for meta-analyses. Such a catalog of significant, evidence-based histopathology patterns from systematic comparisons, and their relevance for different applications, was previously established and repeatedly applied to a wide spectrum of mouse models of pneumonia (12). Here, we propose such a catalog for the reporting of histopathology in SARS-CoV-2–infected hamsters (Table 1) that is based on our previous observations (13) and systematic comparisons with other reports on SARS-CoV2–infected hamsters (8–10), macaques (6, 7), and lesions considered relevant in humans (1–3). Table 1 highlights both the disparity between previous reports on hamsters as well as similarities to and differences from patients with COVID-19. We illustrated our catalog with microphotographs (Figure 1) of the most prominent lesions in hamsters and side-by-side comparisons with similar lesions in humans. Localization of viral RNA by in situ hybridization allows for a concomitant appraisal of the presence of the virus in hamsters (Figures 1W–1Z). The list of relevant lesions (Table 1) and the hamster microphotographs (Figure 1) resulted from a comprehensive study with 24 intranasally infected Syrian hamsters of different ages. Time points of clinical, virological, and pathological examinations ranged from 2 to 14 days postinfection (dpi). Methods are given in the data supplement, and more detailed results were published elsewhere (13). Our study revealed that the observability of most parameters depends on several determinants, primarily the time point after infection. For example, a necrosuppurative bronchitis at 2 dpi turned into a bronchointerstitial pneumonia at 3 dpi. By 5 dpi, a patchy, largely interstitial pneumonia was present with onset of repair and regeneration, followed by almost complete recovery at 14 dpi. Other determinants include the age of the animals (13) and infectious dose used (10). Supposedly, the occurrence, severity, and time course of the different patterns will also be affected by therapeutic interventions and vaccines. Endothelialitis, which is considered important in patients (3) but not previously reported in hamsters, was consistently observed in our study at 5 dpi, albeit without detectable viral RNA in endothelial cells (Figure 1Z). The documentation of endothelialitis clearly increases the value of the hamster model. Also, our finding that young hamsters launch an earlier, stronger, and obviously more effective immune response than older hamsters do (13) makes this model attractive for investigating this issue of high relevance in humans. Likewise, a strong and early influx of granulocytes resembling bacterial infection was observed in our hamsters as described in patients (1, 13). On the other hand, microvascular thrombosis and angiogenesis, both considered relevant in COVID-19 (3), were not yet observed in Syrian hamsters. Nevertheless, lesions with known relevance for patients should be included in such a list with guideline significance to point out differences that could be model specific. Certainly, as our understanding of COVID-19 pathology will increase with time, the catalog of parameters proposed here should be considered preliminary and subject to amendments whenever justified. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern (dgern@thoracic.org).

Hepatic differentiation of human iPSCs in different 3D models: A comparative study.

Abstract: Human induced pluripotent stem cells (hiPSCs) are a promising source from which to derive distinct somatic cell types for in vitro or clinical use. Existent protocols for hepatic differentiation of hiPSCs are primarily based on 2D cultivation of the cells. In the present study, the authors investigated the generation of hiPSC-derived hepatocyte-like cells using two different 3D culture systems: A 3D scaffold-free microspheroid culture system and a 3D hollow-fiber perfusion bioreactor. The differentiation outcome in these 3D systems was compared with that in conventional 2D cultures, using primary human hepatocytes as a control. The evaluation was made based on specific mRNA expression, protein secretion, antigen expression and metabolic activity. The expression of α-fetoprotein was lower, while cytochrome P450 1A2 or 3A4 activities were higher in the 3D culture systems as compared with the 2D differentiation system. Cells differentiated in the 3D bioreactor showed an increased expression of albumin and hepatocyte nuclear factor 4α, as well as secretion of α-1-antitrypsin as compared with the 2D differentiation system, suggesting a higher degree of maturation. In contrast, the 3D scaffold-free microspheroid culture provides an easy and robust method to generate spheroids of a defined size for screening applications, while the bioreactor culture model provides an instrument for complex investigations under physiological-like conditions. In conclusion, the present study introduces two 3D culture systems for stem cell derived hepatic differentiation each demonstrating advantages for individual applications as well as benefits in comparison with 2D cultures.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Long covid-mechanisms, risk factors, and management.

Abstract: Since its emergence in Wuhan, China, covid-19 has spread and had a profound effect on the lives and health of people around the globe. As of 4 July 2021, more than 183 million confirmed cases of covid-19 had been recorded worldwide, and 3.97 million deaths. Recent evidence has shown that a range of persistent symptoms can remain long after the acute SARS-CoV-2 infection, and this condition is now coined long covid by recognized research institutes. Studies have shown that long covid can affect the whole spectrum of people with covid-19, from those with very mild acute disease to the most severe forms. Like acute covid-19, long covid can involve multiple organs and can affect many systems including, but not limited to, the respiratory, cardiovascular, neurological, gastrointestinal, and musculoskeletal systems. The symptoms of long covid include fatigue, dyspnea, cardiac abnormalities, cognitive impairment, sleep disturbances, symptoms of post-traumatic stress disorder, muscle pain, concentration problems, and headache. This review summarizes studies of the long term effects of covid-19 in hospitalized and non-hospitalized patients and describes the persistent symptoms they endure. Risk factors for acute covid-19 and long covid and possible therapeutic options are also discussed.

SARS-CoV-2 is associated with changes in brain structure in UK Biobank

Abstract: There is strong evidence of brain-related abnormalities in COVID-191-13. However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up.

Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments.

Abstract: Long COVID or post-COVID-19 syndrome first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is poorly understood as it affects COVID-19 survivors at all levels of disease severity, even younger adults, children, and those not hospitalized. While the precise definition of long COVID may be lacking, the most common symptoms reported in many studies are fatigue and dyspnoea that last for months after acute COVID-19. Other persistent symptoms may include cognitive and mental impairments, chest and joint pains, palpitations, myalgia, smell and taste dysfunctions, cough, headache, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (e.g. from viral persistence, immune dysregulation, and autoimmunity). The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g. D-dimer, CRP, and lymphocyte count), although more research is required to substantiate such risk factors. While preliminary evidence suggests that personalized rehabilitation training may help certain long COVID cases, therapeutic drugs repurposed from other similar conditions, such as myalgic encephalomyelitis or chronic fatigue syndrome, postural orthostatic tachycardia syndrome, and mast cell activation syndrome, also hold potential. In sum, this review hopes to provide the current understanding of what is known about long COVID.