Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated symptoms, named coronavirus disease 2019 (COVID-19), have rapidly spread worldwide, resulting in the declaration of a pandemic. When several countries began enacting quarantine and lockdown policies, the pandemic as it is now known truly began. While most patients have minimal symptoms, approximately 20% of verified subjects are suffering from serious medical consequences. Co-existing diseases, such as cardiovascular disease, cancer, diabetes, and others, have been shown to make patients more vulnerable to severe outcomes from COVID-19 by modulating host–viral interactions and immune responses, causing severe infection and mortality. In this review, we outline the putative signaling pathways at the interface of COVID-19 and several diseases, emphasizing the clinical and molecular implications of concurring diseases in COVID-19 clinical outcomes. As evidence is limited on co-existing diseases and COVID-19, most findings are preliminary, and further research is required for optimal management of patients with comorbidities.

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes. The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection.

A patient-tailored, ex vivo drug response platform for glioblastoma (GBM) would facilitate therapy planning, provide insights into treatment-induced mechanisms in the immune tumor microenvironment (iTME), and enable the discovery of biomarkers of response. We cultured regionally annotated GBM explants in perfusion bioreactors to assess iTME responses to immunotherapy. Explants were treated with anti-CD47, anti–PD-1, or their combination, and analyzed by multiplexed microscopy [CO-Detection by indEXing (CODEX)], enabling the spatially resolved identification of >850,000 single cells, accompanied by explant secretome interrogation. Center and periphery explants differed in their cell type and soluble factor composition, and responses to immunotherapy. A subset of explants displayed increased interferon-γ levels, which correlated with shifts in immune cell composition within specified tissue compartments. Our study demonstrates that ex vivo immunotherapy of GBM explants enables an active antitumoral immune response within the tumor center and provides a framework for multidimensional personalized assessment of tumor response to immunotherapy.

BackgroundGrowing evidence suggests that the central nervous system is affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), since infected patients suffer from acute and long-term neurological sequelae. Nevertheless, it is currently unknown whether the virus affects the brain cortex. The purpose of this study was to assess the cortical gray matter volume, the cortical thickness, and the cortical surface area in a group of SARS-CoV-2 infected patients with neurological symptoms compared to healthy control subjects. Additionally, we analyzed the cortical features and the association with inflammatory biomarkers in the cerebrospinal fluid (CSF) and plasma.Materials and methodsThirty-three patients were selected from a prospective cross-sectional study cohort during the ongoing pandemic (August 2020–April 2021) at the university hospitals of Basel and Zurich (Switzerland). The group included patients with different neurological symptom severity (Class I: nearly asymptomatic/mild symptoms, II: moderate symptoms, III: severe symptoms). Thirty-three healthy age and sex-matched subjects that underwent the same MRI protocol served as controls. For each anatomical T1w MPRAGE image, regional cortical gray matter volume, thickness, and surface area were computed with FreeSurfer. Using a linear regression model, cortical measures were compared between groups (patients vs. controls; Class I vs. II–III), with age, sex, MRI magnetic field strength, and total intracranial volume/mean thickness/total surface area as covariates. In a subgroup of patients, the association between cortical features and clinical parameters was assessed using partial correlation adjusting for the same covariates. P-values were corrected using a false discovery rate (FDR).ResultsOur findings revealed a lower cortical volume in COVID-19 patients’ orbitofrontal, frontal, and cingulate regions than in controls (p < 0.05). Regional gray matter volume and thickness decreases were negatively associated with CSF total protein levels, the CSF/blood-albumin ratio, and CSF EN-RAGE levels.ConclusionOur data suggest that viral-triggered inflammation leads to neurotoxic damage in some cortical areas during the acute phase of a COVID-19 infection in patients with neurological symptoms.

Importance Growing evidence suggests that coronavirus disease 2019 (COVID-19) is associated with neurological sequelae. However, the underlying pathophysiological mechanisms resulting in central nervous system (CNS) derogation remain unclear. Objective To identify severity-dependent immune mechanisms in the cerebrospinal fluid (CSF) and plasma of COVID-19 patients and their association with brain imaging alterations. Design Prospective cross-sectional cohort study. Setting This study was performed from August 2020 to April 2021. Participants were enrolled in the outpatient clinics, hospital wards and intensive care units (ICU) of two clinical sites in Basel and Zurich, Switzerland. Participants Age >18 years and a positive SARS-CoV-2 test result were inclusion criteria. Potentially matching individuals were identified (n=310), of which 269 declined to participate and 1 did not match inclusion criteria. Paired CSF and plasma samples, as well as brain images, were acquired. The COVID-19 cohort (n=40; mean [SD] age, 54 [20] years; 17 women (42%)) was prospectively assorted by neurological symptom severity (classes I, II and III). Age/sex-matched inflammatory (n=25) and healthy (n=25) CSF and plasma control samples were obtained. For volumetric brain analysis, a healthy age/sex-matched control cohort (n=36) was established. Exposures Lumbar puncture, blood sampling and cranial MRI and/or CT. Main outcomes and measures Proteomics, standard parameters and antibody profiling of paired CSF and plasma samples in COVID-19 patients and controls. Brain imaging and gray matter volumetric analysis in association with biomarker profiles. Follow-up after 10-months. Results COVID-19 patients displayed a plasma cytokine storm but a non-inflammatory CSF profile. Class III patients displayed signs of blood-brain barrier (BBB) impairment and a polyclonal B cell response targeting self- and non-self antigens. Decreased regional brain volumes were present in COVID-19 patients and associated with specific CSF and plasma parameters. Conclusion and relevance Neuro-COVID class III patients had a strong, peripheral immune response resulting in (1) BBB impairment (2) ingress of (auto-)antibodies, (3) microglia activation and neuronal damage signatures. Our data point towards several potentially actionable targets that may be addressed to prevent COVID-19-related neurological sequelae. Trial registration