SARS-COV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice (preprint)

The coronavirus disease of 2019 (COVID-19) pandemic that has led to more than 700 million confirmed cases and near 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains as an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to the neurological complications both acutely and in long COVID.

Treadmill Exercise Stress Echocardiography Exposes Impaired Left Ventricular Function in Patients Recovering from Hospitalization with COVID-19 Without Overt Myocarditis Versus Historical Controls (preprint)

Background: Usual clinical testing rarely reveals cardiac abnormalities persisting after hospitalization for COVID-19. Such testing may overlook residual changes responsible for increased adverse cardiac events post-discharge. Methods: To further elucidate long-term status, we performed exercise stress echocardiography (ESE) in 15 patients age 30-63 without myocarditis 3 to 31 months after hospital discharge. We compared patient outcomes to published data in healthy comparisons (HC) exercising according to the same protocol. Results: Patients' treadmill exercise (Bruce protocol), averaging 8.2 min, was halted by dyspnea or fatigue. Pre-stress baselines in recovering patients (RP) matched HC except for higher heart rate: mean 81 bpm for RP and 63 for HC (p<0.0001). At peak stress, RP had significantly lower mean left ventricular (LV) ejection fraction (67% vs 73%, p<0.0017) and higher peak early mitral inflow velocity/early mitral annular velocity (E/e', 9.1 vs 6.6, p<0.006) compared with HC performing equal exercise (8.5 min). Thus, when stressed, patients without known cardiac impairment showed modest but consistently diminished systolic contractile function and diastolic LV compliance during recovery vs HC. Peak HR during stress was significantly elevated in RP vs HC; peak SBP also trended higher. Average pulmonary artery systolic pressures among RP remained normal. Conclusions: Our measurements during ESE uniquely identified residual abnormality in cardiac contractile function not evident in the unstressed condition. This finding exposes a previously-unrecognized residual influence of COVID-19, possibly related to underlying autonomic dysfunction, microvascular disease, or diffuse interstitial changes after subclinical myocarditis; it may have long-term implications for clinical management and later prognosis.

Digital holo-tomographic 3D maps of COVID-19 microclots in blood to assess disease severity (preprint)

The coronavirus disease 2019 (COVID-19) has impacted health globally. Cumulative evidence points to long-term effects of COVID-19 such as cardiovascular and cognitive disorders diagnosed in patients even after the recovery period. In particular, micrometer-sized blood clots and hyperactivated platelets have been identified as potential indicators of long COVID. Here we resolve individual microclot structures in platelet-rich plasma of donors with different subphenotypes of COVID-19 in a label-free manner, using 3D digital holo-tomographic microscopy (DHTM). Based on 3D refractive index (RI) tomograms, the size, dry mass, and prevalence of microclot composites were quantified and then parametrically differentiated from fibrin-rich microclots and platelet aggregates in the plasma of COVID-19 donors. Importantly, fewer microclots and platelet aggregates were detected in the plasma of healthy controls when compared to COVID-19 donors. Our work highlights the utility of integrating DHTM in clinical settings that may allow the detection of individuals at risk of developing microvascular thrombotic disorders and for monitoring the efficiency of prescribed treatments by screening plasma samples.

Long-term outcomes of hospitalized SARS-CoV-2/COVID-19 patients with and without neurological involvement: 3-year follow-up assessment (preprint)

Background and ObjectivesAcute neurological manifestations are a common complication of acute COVID-19 disease. This study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. MethodsPatients infected by SARS-CoV-2 between March 1 and April 16, 2020 and hospitalized in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to January 23, 2023 (3 years post COVID-19). This cohort consisted of 414 COVID-19 patients with significant neurological manifestations and 1199 propensity-matched COVID- 19 patients without neurological manifestations. Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were clinical neuroimaging findings (hemorrhage, active stroke, prior stroke, mass effect, and microhemorrhage, white-matter changes, microvascular disease, and volume loss). Predictive models were used to identify risk factors of mortality post-discharge. ResultsMore patients in the neurological cohort were discharged to acute rehabilitation (10.54% vs 3.68%, p<0.0001), skilled nursing facilities (30.67% vs 20.78%, p=0.0002) and fewer to home (55.27% vs 70.21%, p<0.0001) compared to the matched controls. Incidence of readmission for any medical reason (65.70% vs 60.72%, p=0.036), stroke (6.28% vs 2.34%, p<0.0001), and MACE (20.53% vs 16.51%, p=0.032) was higher in the neurological cohort post-discharge. Neurological patients were more likely to die post-discharge (58 (14.01%) vs 94 (7.84%), p=0.0001) compared to controls (HR=2.346, 95% CI=(1.586, 3.470), p<0.0001). The major causes of death post-discharge were heart disease (14.47%), sepsis (13.82%), influenza and pneumonia (11.18%), COVID-19 (8.55%) and acute respiratory distress syndrome (7.89%). Factors associated with mortality after leaving the hospital were belonging to the neurological cohort (OR=1.802 (1.237, 2.608), p=0.002), discharge disposition (OR=1.508, 95% CI=(1.276, 1.775), p<0.0001), congestive heart failure (OR=2.281 (1.429, 3.593), p=0.0004), higher COVID-19 severity score (OR=1.177 (1.062, 1.304), p=0.002), and older age (OR=1.027 (1.010, 1.044), p=0.002). There were no group differences in gross radiological findings, except the neurological cohort showed significantly more age-adjusted brain volume loss (p<0.05) compared to controls. DiscussionCOVID-19 patients with neurological manifestations have worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for COVID-19 patients with neurological manifestations.

Microvascular Disease and Severe COVID-19 Outcomes in UKBiobank Diabetic Cohort (preprint)

Background: Early in the COVID-19 pandemic, evidence emerged to suggest that people with diabetic retinopathy (DR) or other microvascular diseases were at greater risk of severe short-term outcomes. Evaluation of outcomes over the longer term and more generalisable evidence were needed. Methods: We identified a cohort of UKBiobank participants with diabetes and retrieved their diagnostic codes for a variety of microvascular diseases, other diabetic complications and systemic comorbidities from hospital admissions data. We investigated the relationship between these diagnoses and the study outcome: admission to Critical Care or death from COVID-19, taking age, sex and diabetes duration into account. We tested the relationships further by adding more baseline covariates, and weighting diagnostic codes according to their recency prior to testing positive for COVID-19.Findings: In univariate analyses, DR (OR: 1·519, p= 0·016) and microvascular disease (OR: 2·001, p=0·000) were both associated with greater risk of the study outcome. In multivariate analyses, as may be expected, respiratory disease was the comorbidity most strongly associated with the study outcome, with microvascular disease second. Adjusting the analyses by number of hospital admissions (a proxy for general health) and weighted diagnostic coding (an indicator of comorbidity recency or severity at the time of COVID-19 diagnosis), did not improve the predictive power of the model.Interpretation: The presence of microvascular disease in routinely-collected healthcare data predicts the risk of severe outcomes of COVID-19, independently of general health, in a diabetic cohort. Funding Information: This work was supported by a grant from Diabetes UK (20/0006221). The funders did not influence the study design or methodology.Declaration of Interests: The authors declare no conflict of interest.

COVID-19 patients in the COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx (preprint)

BACKGROUND: Early in the pandemic, we established COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx and implemented a detailed evaluation protocol was implemented to assess physical, emotional, and cognitive function, pulmonary function tests, and imaging for COVID-19 survivors. Here we report our findings five months post-acute COIVD-19. METHODS: Main outcomes and measures included pulmonary function tests, imaging tests, and a battery of symptom, physical, emotional, and cognitive assessments 5 months post-acute COVID-19. FINDINGS: Dyspnea, fatigue, decreased exercise tolerance, brain fog, and shortness of breath were the most common symptoms but there were generally no significant differences between hospitalized and non-hospitalized cohorts (p>0.05). Many patients had abnormal physical, emotional, and cognitive scores, but most functioned independently; there were no significant differences between hospitalized and non-hospitalized cohorts (p>0.05). Six-minute walk test, lung ultrasound, and diaphragm excursion were abnormal but only in the hospitalized cohort. Pulmonary function tests showed moderately restrictive pulmonary function only in the hospitalized cohort but no obstructive pulmonary function. Newly detected major neurological events, microvascular disease, atrophy, and white-matter changes were rare, but lung opacity and fibrosis-like findings were common after acute COVID-19. INTERPRETATION: Many COVID-19 survivors experienced moderately restrictive pulmonary function, and significant symptoms across the physical, emotional, and cognitive health domains. Newly detected brain imaging abnormalities were rare, but lung imaging abnormalities were common. This study provides insights into post-acute sequelae following SARS-CoV-2 infection in neurological and pulmonary systems which may be used to support at-risk patients, develop effective screening methods and interventions.

Evaluation of endogenous and therapeutic 25-hydroxycholesterols in murine models of pulmonary SARS-CoV-2 infection (preprint)

Oxysterols (i.e., oxidized cholesterol species) have complex roles in biology. 25-hydroxycholesterol (25HC), a product of activity of cholesterol-25-hydroxylase (CH25H) upon cholesterol, has recently been shown to be broadly antiviral, suggesting therapeutic potential against SARS-CoV-2. However, 25HC can also amplify inflammation and tissue injury and be converted by CYP7B1 to 7,25HC, a lipid with chemoattractant activity via the G protein-coupled receptor, EBI2/GPR183. Here, using in vitro studies and two different murine models of SARS-CoV-2 infection, we investigate the effects of these two oxysterols on SARS-CoV-2 pneumonia. We show that while 25HC and enantiomeric-25HC are antiviral in vitro against human endemic coronavirus-229E, they did not inhibit SARS-CoV-2; nor did supplemental 25HC reduce pulmonary SARS-CoV-2 titers in the K18-human ACE2 mouse model in vivo. 25HC treatment also did not alter immune cell influx into the airway, airspace cytokines, lung pathology, weight loss, symptoms, or survival but was associated with increased airspace albumin, an indicator of microvascular injury, and increased plasma pro-inflammatory cytokines. Conversely, mice treated with the EBI2/GPR183 inhibitor NIBR189 displayed a modest increase in lung viral load only at late time points, but no change in weight loss. Consistent with these findings, although Ch25h was upregulated in the lungs of SARS-CoV-2-infected WT mice, lung viral titers and weight loss in Ch25h-/- and Gpr183-/- mice infected with the beta variant were similar to control animals. Taken together, endogenous 25-hydroxycholesterols do not significantly regulate early SARS-CoV-2 replication or pathogenesis and supplemental 25HC may have pro-injury rather than therapeutic effects in SARS-CoV-2 pneumonia.

Longitudinal lung function assessment of patients hospitalised with COVID-19 using 1H and 129Xe lung MRI (preprint)

Introduction: Microvascular abnormalities and impaired 129Xe gas transfer have been observed in patients with COVID 19. The progression of pathophysiological pulmonary changes during the post acute period in these patients remains unclear. Methods: Patients who were hospitalised due to COVID 19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25 and 50 weeks after hospital admission. The imaging protocol included: ultra short echo time, dynamic contrast enhanced lung perfusion, 129Xe lung ventilation, 129Xe diffusion weighted and 129Xe 3D spectroscopic imaging of gas exchange. Results: 9 patients were recruited and underwent MRI at 6 (n=9), 12 (n=9), 25 (n=6) and 50 (n=3) weeks after hospital admission. At 6 weeks after hospital admission, patients demonstrated impaired 129Xe gas transfer (RBC:M) but normal lung microstructure (ADC, LmD). Minor ventilation abnormalities present in four patients were largely resolved in the 6 to 25 week period. At 12 week follow up, all patients with lung perfusion data available (n=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 and 25 week follow up, significant improvements in 129Xe gas transfer were observed compared to 6 week examinations, however 129Xe gas transfer remained abnormally low. Conclusions: This study demonstrates that multinuclear MRI is sensitive to functional pulmonary changes in the follow up of patients who were hospitalised with COVID 19. Persistent impairment of xenon transfer may represent a physiological mechanism underlying ongoing symptoms in some patients and may indicate damage to the pulmonary microcirculation.

Microvascular Injury With Secondary Edema, Bronchoconstriction and Vasoconstriction of Non-involved Lung Parenchymal Segments May Contribute to Clinical Deterioration of Non-critically Ill Patients Hospitalized for SARS-CoV-2 Pneumonia Without Evidence of Pulmonary Embolism: A Preliminary Study. (preprint)

Purpose: We aimed to better understand the pathophysiology of SARS-CoV-2 pneumonia in non-critically ill hospitalized patients secondarily presenting with clinical deterioration and increase in oxygen requirement. Methods: : We consecutively enrolled patients without clinical or biological evidence for superinfection, without left ventricular (LV) dysfunction and for whom a pulmonary embolism was discarded by computed tomography pulmonary angiography. We investigated lung ventilation and perfusion (LVP) by LVP scintigraphy, and, 24 hours later, left and right ventricular function by 99m Tc-labelled albumin gated-blood-pool scintigraphy with late (60 mn) tomographic albumin images on the lungs to evaluate lung albumin retention that could indicate microvascular injuries with secondary edema. Results: : We included 13 patients with confirmed SARS-CoV-2 pneumonia. All had CT evidence of organizing pneumonia and normal LV ejection fraction.No patient demonstrated preserved ventilation with perfusion defect (mismatch), which may eliminate a distal lung thrombosis. Patterns of ventilation and perfusion were heterogeneous with sometimes healthy lung segments paradoxically hypoperfused and hypoventilated while both normal perfusion and ventilation were maintained in segments with organizing pneumonia (n=4). Lung albumin retention in area of organizing pneumonia was observed in 9 patients, indicating microvascular injuries, vessel permeability increase and secondary edema. Conclusion: In hospitalized non-critically ill patients without pulmonary embolism or LV dysfunction, various types of damage may contribute to clinical deterioration including microvascular injuries and secondary edema, broncho and vasoconstriction of area not involved by organizing pneumonia while no evidence was found for significant distal thrombosis detectable by LVP scintigraphy.

Immune profile of children with post-acute sequelae of SARS-CoV-2 infection (Long Covid) (preprint)

There is increasing reporting by patients organization and researchers of long covid (or post-acute sequelae of SARS-CoV-2 - PASC), characterized by symptoms such as fatigue, dyspnea, chest pain, cognitive and sleeping disturbances, arthralgia and decline in quality of life. Immune system dysregulation with a hyperinflammatory state, direct viral toxicity, endothelial damage and microvascular injury have been proposed as pathologenic mechanisms. Recently, cohorts of children with PASC have been reported in Italy, Sweden and Russia. However, immunological studies of children with PASC have never been performed. In this study, we documented significant immunologic differences between children that completely recovered from acute infection and those with PASC, providing the first objective laboratory sign of the existence of PASC in children.

Acute Endotheliitis (Type 3 Hypersensitivity Vasculitis) in Ten COVID-19 Autopsy Brains (preprint)

Central nervous system (CNS) involvement in COVID-19 may occur through direct SARS-CoV-2 invasion through peripheral or cranial nerves or through vascular endothelial cell infection. The renin-angiotensin system may play a major part in CNS morbidity. Effects of hypoxia have also been implicated in CNS lesions in COVID-19. This communication reports on ten consecutive autopsies of individuals with death due to COVID-19 with decedent survival ranging from 30 minutes to 84 days after admission. All ten brains examined had neutrophilic microvascular endotheliitis present in variable amounts and variably distributed. Importantly, this acute stage of type 3 hypersensitivity vasculitis can be followed by fibrinoid necrosis and inner vascular wall sclerosis, but these later stages were not found. These results suggest that a vasculitis with autoimmune features occurred in all ten patients. It is possible that viral antigen in or on microvascular walls or other antigen-antibody complexes occurred in all ten patients proximate to death as a form of autoimmune vasculitis.

Are Aspirin and Apixaban Sufficient to Prevent Immunothrombosis in COVID-19? (preprint)

Severe COVID-19 disease is associated with respiratory and vascular injury and microvascular immunothrombosis mediated by complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion and activation of coagulation cascade. Amongst the inflammatory lipids, thromboxane A2 (TxA2) is a known key mediator of microvascular thrombosis. The levels of TxB2, a stable metabolite of TxA2 are markedly increased in the bronchoalveolar lavage fluid and plasma in severe COVID-19 patients. Low-dose aspirin mitigates the generation of prostanoids including TxA2 by irreversible inactivation of the constitutive enzyme cyclooxygenase (COX)-1. The anti-thrombotic action of aspirin is currently being investigated in outpatient and hospitalized COVID-19 patients in the global RECOVERY and ACTIV-4 clinical trials. Several lines of investigations suggest that COX-2 plays an important and critical role in the immunothrombotic effects mediated by COVID-19. Pharmacologic inhibition of either COX-1 or COX-2 can prevent a plethora of lipid mediators of inflammation that are both pro- and anti-inflammatory in function. Thus, a more definitive approach to prevent immunothrombotic events in COVID-19 will be to directly block the prothrombotic effects of TxA2. Although thromboxane synthase (TS) inhibitors suppress TxA2 formation, accumulation of the substrate PGH2 is known to interact with the platelet and vessel wall TxA2 prostanoid receptor (TPR), thus reducing the antiplatelet effects of TS inhibitors. TPR antagonists block the activity of both TxA2 and PGH2 on platelets and vessels but do not block TxA2 production, which leads to increased generation of 11-dehydro-thromboxane B2, a stable metabolite of TxA2, and a potent agonist of the DP2 (CRTH2) receptor for prostaglandin D2 (PGD2). PGD2/DP2 receptor signaling has been implicated in immune dysregulation in viral infections including COVID-19. Ramatroban, an orally bioavailable, potent, dual TxA2/TP and PGD2/DP2 receptor antagonist, has demonstrated efficacy in a variety of animal models of atherosclerosis, thrombosis and sepsis. Ramatroban has a proven safety profile, having been used in Japan over the past 20 years as a treatment of allergic rhinitis and therefore, merits investigation as a promising antithrombotic and immunomodulator agent for chemoprophylaxis and treatment in COVID-19 patients.

The SARS-CoV-2 spike protein disrupts the cooperative function of human cardiac pericytes - endothelial cells through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease (preprint)

Background: Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses primarily the capsid spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known if the S protein alone, without the other viral elements, is able to trigger vascular cell signalling and provoke cell dysfunction. Methods: We investigated the effects of the recombinant, stabilised S protein on primary human cardiac pericytes (PCs) signalling and function. Endpoints included cell viability, proliferation, migration, cooperation with endothelial cells (ECs) in angiogenesis assays, and release of pro-inflammatory cytokines. Adopting a blocking strategy against the S protein receptors ACE2 and CD147, we explored which receptor mediates the S protein signalling in PCs. Findings: We show, for the first time, that the recombinant S protein alone elicits functional alterations in cardiac PCs. This was documented as: (1) increased migration, (2) reduced ability to support EC network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm; and (4) production of pro-apoptotic factors responsible for EC death. Furthermore, the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in cardiac PCs. Accordingly, the neutralization of CD147, using a blocking antibody, prevented the activation of ERK1/2 and partially rescued the PC function in the presence of the S protein. Interpretation: Our findings suggest the new, intriguing hypothesis that the S protein may elicit vascular cell dysfunction, potentially amplifying, or perpetuating, the damage caused by the whole coronavirus. This mechanism may have clinical and therapeutic implication.

Microvascular Angiopathic Consequences of COVID-19 (preprint)

The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first appeared in Wuhan, China in December, 2019. Ever increasing data is emerging about COVID-19 and its effects on the arterial and venous circulation. Clinical features associated with COVID-19 suggest that endothelial cell dysfunction and microvascular thrombosis are to a large part contributing to resultant multi-organ complications. This review is aimed at highlighting the critical aspects associated with COVID-19 and its presumed microvascular angiopathic complications leading to multi-organ dysfunction.

Clinico-pathological features in fatal Covid-19 Infection: A Preliminary Experience of a Tertiary Care Centre in North India using Post-Mortem Minimally Invasive Tissue Biopsies (preprint)

Background: The Covid-19 pandemic began in China in December 2019. India is the second most affected country, as of November 2020 with more than a 8.5million cases. Covid-19 infection primarily involves the lung with the severity of illness varying from influenza-like illness to acute respiratory distress syndrome. Other organs have also found to be variably affected. Studies evaluating the histopathological changes of Covid-19 are critical in providing a better understanding of the disease pathophysiology and guiding treatment. Minimally invasive biopsy techniques (MITS/B) provide an easy and suitable alternative to complete autopsies. In this prospective single-center study we present the histopathological examination of 37 patients who died with complications of Covid-19. Methods: This was an observational study conducted in the Intensive Care Unit of JPN Trauma Centre AIIMS. A total of 37 patients who died of Covid-19 were enrolled in the study. Post-mortem percutaneous biopsies were taken with the help of surface landmarking/ultrasonography guidance from lung, heart, liver, and kidneys; after obtaining ethical consent. The biopsy samples were then stained with haematoxylin and eosin stain. Immunohistochemistry (IHC) was performed using CD61 and CD163 in all lung cores. SARS-CoV-2 virus was detected using IHC with primary antibodies in selected samples. Details regarding demographics, clinical parameters, hospital course, treatment details, and laboratory investigations were also collected for clinical correlation. Results: A total of 37 patients underwent post-mortem minimally invasive tissue sampling. Mean age of the patients was 48.7years and 59.5% of them were males. Respiratory failure was the most common complication seen in 97.3%. Lung histopathology showed acute lung injury and diffuse alveolar damage in 78% of patients. Associated bronchopneumonia was seen in 37.5% of patients and scattered microthrombi were visualized in 21% of patients. Immunostaining with CD61 and CD163 highlighted megakaryocytes and increased macrophages in all samples. Immunopositivity for SARS-CoV-2 was observed in Type II pneumocytes. Acute tubular injury with epithelial vacuolization was seen in 46% of the renal biopsies but none of them showed evidence of microvascular thrombosis. 71% of the liver tissue cores showed evidence of Kupfer cell hyperplasia. 27.5% had evidence of submassive hepatic necrosis and 14% had features of acute on chronic liver failure. All the heart biopsies showed non-specific features such as hypertrophy with nucleomegaly with no evidence of myocardial necrosis in any of the samples. Conclusions The most common finding in this cohort is the diffuse alveolar damage with demonstration of SARS-CoV-2 protein in the acute phase of DAD. Microvascular thrombi were rarely identified in the lung, liver and kidney. Substantial hepatocyte necrosis, hepatocyte degeneration, Kupffer cell hypertrophy, micro, and macrovesicular steatosis unrelated to microvascular thrombi suggests that liver might be a primary target of Covid-19. This study highlights the importance of MITS/B in better understanding the pathological changes associated with Covid-19.

Early detection and Successful Management of Acute Mesenteric Ischaemia in symptomatic COVID 19 patient (preprint)

Newer evidence states that COVID 19 pneumonia induces a hypercoagulable state leading to vascular and microvascular thrombotic events. Acute mesenteric ischemia (AMI) is a potentially fatal vascular emergency with overall mortality of 60% to 80%. [1] However till date, only few cases of SMA thrombosis in COVID-19 positive patients are reported and most have succumbed to COVID-19 or mesenteric ischaemia. [2-4] Physicians treating COVID 19 usually treat respiratory symptoms and may completely overlook any other uncommon pathology. This case report emphasises that a patient with early detection and management of acute mesenteric ischaemia being symptomatic for COVID 19 can avoid major bowel surgery and negate any morbidity or mortality associated with the same.

Cerebral Microvascular Injury in Severe COVID-19 (preprint)

IMPORTANCE: Microvascular lesions are common in patients with severe COVID-19. Radiologic-pathologic correlation in one case suggests a combination of microvascular hemorrhagic and ischemic lesions that may reflect an underlying hypoxic mechanism of injury, which requires validation in larger studies. OBJECTIVE: To determine the incidence, distribution, and clinical and histopathologic correlates of microvascular lesions in patients with severe COVID-19. DESIGN: Observational, retrospective cohort study: March to May 2020. SETTING: Single academic medical center. PARTICIPANTS: Consecutive patients (16) admitted to the intensive care unit with severe COVID-19, undergoing brain MRI for evaluation of coma or focal neurologic deficits. EXPOSURES: Not applicable. MAIN OUTCOME AND MEASURES: Hypointense microvascular lesions identified by a prototype ultrafast high-resolution susceptibility-weighted imaging (SWI) MRI sequence, counted by two neuroradiologists and categorized by neuroanatomic location. Clinical and laboratory data (most recent measurements before brain MRI). Brain autopsy and cerebrospinal fluid PCR for SARS-CoV 2 in one patient who died from severe COVID-19. RESULTS: Eleven of 16 patients (69%) had punctate and linear SWI lesions in the subcortical and deep white matter, and eight patients (50%) had >10 SWI lesions. In 4/16 patients (25%), lesions involved the corpus callosum. Brain autopsy in one patient revealed that SWI lesions corresponded to widespread microvascular injury, characterized by perivascular and parenchymal petechial hemorrhages and microscopic ischemic lesions. CONCLUSIONS AND RELEVANCE: SWI lesions are common in patients with neurological manifestations of severe COVID-19 (coma and focal neurologic deficits). The distribution of lesions is similar to that seen in patients with hypoxic respiratory failure, sepsis, and disseminated intravascular coagulation. Collectively, these radiologic and histopathologic findings suggest that patients with severe COVID-19 are at risk for multifocal microvascular hemorrhagic and ischemic lesions in the subcortical and deep white matter.