Multifactorial Effects of Covid-19: A Review of Published Autopsy Reports

Introduction: SARS-CoV-2 is responsible for the current global pandemic. SARS-CoV-2 infection underlies the novel viral condition coronavirus disease 2019 (COVID-19). COVID-19 causes significant pulmonary sequelae contributing to serious morbidities. The pathogenesis of COVID-19 is complex with a multitude of factors leading to varying levels of injury numerous extrapulmonary organs. This review of 124 published articles documenting COVID- 19 autopsies included 1,142 patients. Method(s): A PubMed search was conducted for COVID-19 autopsy reports published before March 2021 utilizing the query COVID-19 Autopsy. There was no restriction regarding age, sex, or ethnicity of the patients. Duplicate cases were excluded. Findings were listed by organ system from articles that met selection criteria. Result(s): Pulmonary pathology (72% of articles;866/1142 patients): diffuse alveolar damage (563/866), alveolar edema (251/866), hyaline membrane formation (234/866), type II pneumocyte hyperplasia (165/866), alveolar hemorrhage (164/866), and lymphocytic infiltrate (87/866). Vascular pathology (41% of articles;771/1142 patients): vascular thrombi (439/771)-microvascular predominance (294/439)-and inflammatory cell infiltrates (116/771). Cardiac pathology (41% of articles;502/1142 patients): cardiac inflammation (186/502), fibrosis (131/502), cardiomegaly (100/502), hypertrophy (100/502), and dilation (35/502). Hepatic pathology (33% of articles;407/1142 patients): steatosis (106/402) and congestion (102/402). Renal pathology (30% of articles;427/1142 patients): renal arteries arteriosclerosis (111/427), sepsis-associated acute kidney injury (81/427) and acute tubular necrosis (77/427). Conclusion(s): This review revealed anticipated pulmonary pathology, along with significant extrapulmonary involvement secondary to COVID-19, indicating widespread viral tropism throughout the human body. These diverse effects require additional comprehensive longitudinal studies to characterize short-term and long-term COVID-19 sequelae and inform COVID-19 treatment.

Lung pathology

The series of autopsies reported since the beginning of the pandemic have highlighted several patterns of lung damage, both isolated and combined. The factors influencing the occurrence of these different tissue responses to viral aggression by SARS-CoV-2 have not yet been determined. In asymptomatic patients or patients with respiratory symptoms who were not ventilated, lymphocyte pneumonia associated with type II pneumocyte atypical hyperplasia and a few hyaline membranes or focal lesions of acute fibrinous pneumonia have been observed. In critically ill patients, the most frequent pattern is diffuse alveolar damage with interstitial lymphoid infiltration, type II pneumocyte atypia and, very often, capillary or arteriolar microthromboses and/or endothelitis. The precise description of these lesions, which is becoming more and more consensual, makes it possible to understand the favourable effects of corticosteroid therapy in seriously ill patients and the evolution under ventilation towards fibrosis.Copyright © ERS 2021.

SARS-CoV-2 BA.5 CAUSES HIGHER REPLICATION AND LETHAL INFECTION IN K18-hACE2 MICE

Background: The continuous evolution of SARS-CoV-2 in the diverse immune landscape (natural, vaccine, hybrid) is giving rise to novel immune escape mutations. So far, the resulting new variants (BA.1, BA.2, BA.2.12.1) were observed to cause mild infections, however, BA.5 infections are associated with an increased risk of hospitalization.1 Therefore it is essential to investigate the pathogenesis of BA.5. Method(s): Here we compared the pathogenicity of Pre-Omicron (B.1.351) and Omicron (BA.1, BA.2.12.1, and BA.5) variants in wild-type C57BL/6J mice and K18-hACE2 mice. The virus replication kinetics was also studied in human Calu3, pulmonary alveolar type 2 (AT2) cells, and airway organoids (HAO). Cell-to-cell spread of virus was measured by syncytia formation assay and immunohistochemistry (IHC) of infected lungs. Result(s): In the results, infection in C57BL/6J mice showed severe weight loss ( >15%) for B.1.351 infected mice and moderate ( >5%) for BA.5 infected. C57BL/6J mice showed higher virus replication of B.1.351 followed by BA.5, BA.1, and BA.2.12.1. At the peak of virus replication (2 days) plaque-forming units from lung extract of BA.5 infected mice were two, and three logs higher compared to BA.1 and BA.2.12.1 respectively. BA.5 infection was lethal to 80% of infected K18-hACE2 mice, whereas the mice looked normal after infection with BA.1 and BA.2.12.1. BA.5 infected mice showed high virus replication in brain tissue. Surprisingly the syncytia formation assay and IHC for BA.5 was comparable to that of B.1.351, indicating the higher cell-to-cell spread of BA.5 and B.1.351 compared to BA.1 and BA.2.12.1, which is one of the measures of pathogenicity. Calu3 and HAO showed the same trend of virus replication as was observed in-vivo experiments however AT2 cells were found to be resistant to BA.5 replication. Conclusion(s): These results suggest that the BA.5 variant (lineage) of Omicron has the potential to regain the pathogenicity as it shows increased virulence compared to other Omicron sub-variants. Lethal infection of BA.5 in K18-hACE2 mice may be attributed to catastrophic encephalitis and increased cell-to-cell spread.

COVID-19 disease and hereditary angioedema

Since December 2019, an outbreak of a novel coronavirus (SARS-CoV-2) infection causing COVID-19 disease has influenced the whole world. Angiotensin converting enzyme 2 (ACE2) receptors on type 2 pneumocytes in humans were determined as the entry for SARSCoV-2. Receptor binding and subsequently endocytosis of ACE2 diminish the cell membrane expression and also the function of ACE2. ACE2 is an enzyme involved in bradykinin metabolism. Lys-des-Arg9-BK occured with enzymatic cleaving of Lys-BK derived from low molecular weight kininogen is inactivated by ACE2 in tissues and it is a vasodilator agent having its own receptor named bradykinin B1. Non-metabolized Lys-des-Arg9-BK can be the reason for tissue vasodilation and increased vascular permeability in the patients with COVID-19. Increased bradykinin levels in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) do not cause increased SARS-CoV-2 infection or more severe disease. Although SARS-CoV-2 infection does not result in increased bradykinin levels, it can increase Lys-des-Arg9-BK levels.Copyright © 2020 Bilimsel Tip Yayinevi. All rights reserved.

Hypothesis of a potential antiviral drug

The approval of mRNA vaccine technique against COVID-19 opens a door to research and the creation of new drugs against different infectious pathologies or even cancer, since for several diseases the therapeutic options are limited, and different viral diseases are treated only symptomatically. For these reasons, this study proposed a hypothesis supported by biological studies, that it provides a theoretical basis for the possible development of a drug that used the mRNA technique and the ribonucleolytic action of a ribonuclease for a possible antiviral therapy, and analyzed a future perspective of this technique in order to provide a bibliographic basis on this hypothesis and motivate researchers to carry out biological studies on this topic.Copyright © 2022, Health Biotechnology and Biopharma. All rights reserved.

Associations between brain gene expression perturbations implicated by COVID-19 and psychiatric disorders.

BACKGROUND: Currently, there is increasing evidence from clinic, epidemiology, as well as neuroimaging, demonstrating neuropsychiatric abnormalities in COVID-19, however, whether there were associations between brain changes caused by COVID-19 and genetic susceptibility of psychiatric disorders was still unknown. METHODS: In this study, we performed a meta-analysis to investigate these associations by combing single-cell RNA sequencing datasets of brain tissues of COVID-19 and genome-wide association study summary statistics of psychiatric disorders. RESULTS: The analysis demonstrated that among ten psychiatric disorders, gene expression perturbations implicated by COVID-19 in excitatory neurons of choroid plexus were significantly associated with schizophrenia. CONCLUSIONS: Our analysis might provide insights for the underlying mechanism of the psychiatric consequence of COVID-19.

Developing advanced cell culture models to study COVID19-associated pulmonary fibrosis

Patients with severe COVID-19-associated pneumonia are at risk to develop pulmonary fibrosis. To study the underlying mechanisms, we aim to develop advanced cell culture models that reliably reflect COVID-19-related profibrotic microenvironment. To identify key cellular players, we performed pilot immunohistochemistry analysis on lung tissue from COVID-19 patients with fibrosis collected during autopsy. Results revealed diffuse alveolar damage with macrophage infiltration, and myofibroblast accumulation with enriched collagen deposition surrounding the damaged alveoli. To mimic SARS-CoV-2 infection in alveoli, we infected human primary type II alveolar epithelial cells (AEC2) and found enhanced signaling of profibrotic cytokine transforming growth factor beta (TGFbeta) in some donors. To recreate the early fibrotic niche, an alveolar-macrophage-fibroblast (AMF) tri-culture model was established. After infecting AEC2 with SARS-CoV-2 in this AMF model, gene expression analysis provided evidence for fibroblast-to-myofibroblast transition. Furthermore, we found that overexpression of SARS-CoV-2 papain-like protease (PLpro) can promote TGFbeta signaling in HEK293T and A549 cells. After infecting AEC2 with SARS-CoV-2 PLpro lentivirus in the AMF model, we found signs of epithelial-to-mesenchymal transition and fibroblast-to myofibroblast transition. In future studies, we will use a detailed analysis of COVID-19-associated lung fibrosis with other types of lung fibrosis, to further refine COVID-19-related fibrosis models, including lung-on-chip models.

The effect of ACE inhibitors on inflammation and clinical end-points in COVID-19 patients Relationship of ACE inhibitors to COVID-19 patients

Aim: COVID-19 infection has affected the whole world. It has been speculated that the virus might hold on to angiotensin-converting enzyme 2 (ACE 2) surfaces of type 2 alveolar cells. ACE inhibitors and angiotensin receptor antagonists (ARBs) are essential antihypertensive and cardiac failure drugs in the guidelines. In this study, we aimed to find the effect of these drugs on clinical, laboratory courses, and outcomes of COVID-19 patients. Material(s) and Method(s): We included 109 patients in this study. There were 43 patients in the ACE/ARB group and 66 patients in the non-ACE/ARB group. The mean age was 60 years in the ACE/ARB group and 52 years old in the non-ACE/ARB group. Basal symptoms, hemogram, CRP, D-dimer, LDH, Ferritin, AST, duration of hospitalization, percentage of intensive care unit (ICU) need, length of stay in ICU were compared between the groups. Result(s): The mean age in the ACE/ARB group was higher than in the other group and was statistically significant (p=.027). The initial symptoms were not different. There were no differences between the laboratory results of the groups. The ICU need was higher in the patients who do not use the drug than in the users (p<.020). Discussion(s): ACE/ARB usage in COVID-19 patients did not worsen the course of the disease. However, ACE/ARB users before COVID-19 pandemic were taken to ICU at a low rate.Copyright © 2022, Derman Medical Publishing. All rights reserved.

COVID-19 Pandemic: Current Scenario, Challenges and Future Perspectives

Background: The new public health emergency of COVID-19 caused by a novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which originated in Wuhan, Hubei province, China in December 2019, evolved into a pandemic in no time and is still in progression. The novel virus mainly targets the lower respiratory system, leading to viral pneumonia, with other associated complications of multi organ failure. Discussion(s): The bats, in particular Rhinolophus affinis, is a natural host of SARS-CoV-2 and the virus is considered to have spread to humans through yet controversial intermediate host pangolins. The incubation period ranges from 2-14 days and mode of person-to-person transmission is primari-ly via the direct contact with the infected person or through the droplets generated by the infected person during coughing or sneezing. The initiation of the infection process by SARS-CoV-2 virus is the invasion of lung type II alveolar cells via a receptor protein called angiotensin-converting enzyme 2 (ACE2) present on the cell membrane with glycosylated spike (S) viral protein that medi-ates host cell invasion. The main diagnostic tools employed are molecular methods based on nucleic acid detection engaging real-time quantitative polymerase chain reaction (RT-qPCR) and a new immunoassays based on antibodies IgM/IgG. Conclusion(s): Due to the lack of specific clinically approved anticovid-19 drugs or vaccines that could be used for its prevention or treatment, the current management approach is essentially sup-portive and symptomatic. The precautionary measures like, social distancing, cleaning hands with soap or sanitizers, using disinfectant solutions to decontaminate the surfaces of things and proper ventilation, wearing masks and other protective gears to curb transmission. The knowledge regard-ing COVID-19 therapies is still evolving and collaborative efforts are being put in to discover definitive therapies on different themes in the form of vaccines, repurposing drugs, RNA interfer-ence, docking studies, etc.Copyright © 2021 Bentham Science Publishers.

Synthetic Lung Surfactant Treatment for COVID-19 Pneumonia

COVID-19 has led to morbidity in millions of patients, ranging from mild flu-like symptoms to severe respiratory failure, necessitating oxygen supplementation and mechanical ventilation, and ultimately death. The SARS-CoV-2 virus reacts with angiotensin-converting enzyme 2 (ACE2) molecules that are especially found in alveolar epithelial type 2 cells in the lungs and thereby causes a loss in lung surfactant, a protein-lipid mixture that is crucial for both native immunity and reduction of surface ten-sion in the lung alveoli. Lung surfactant insufficiency results in atelectasis and loss of functional lung tissue amid an inflammatory storm and may be countered by treating COVID-19 pneumonia patients with exogenous lung surfactant, preferably by aerosol delivery of a novel dry powder synthetic lung sur-factant. More research on timing, dosing, and delivery of synthetic lung surfactant in patients with COVID-19 pneumonia is of crucial importance to implement this approach in clinical practice.Copyright © 2021 Bentham Science Publishers.

Human induced pluripotent stem cell-derived alveolar type 2 cells mature at air-liquid interface and respond to airborne stimuli

Human alveolar type II cells (AT2s) are progenitors of the alveolar epithelium and are among the pulmonary cells that are directly exposed to inhaled stimuli. Primary human AT2s can be cultured in three-dimensional alveolospheres, but are difficult to culture in the physiologically relevant air-liquid interface (ALI) format. Human induced pluripotent stem cells (iPSCs) can be directed to differentiate to iPSC-derived AT2s (iAT2s) in alveolospheres, where they transcriptomically resemble fetal lung. Here we report the successful adaptation of iAT2s to ALI culture, which promotes their maturation and permits exposure to inhaled stimuli. We transcriptomically profile iAT2s cultured at ALI and find that they mature as they downregulate cell cycle-associated transcripts. We then evaluate the extent of iAT2 maturation at ALI within the developmental context by comparison to primary AT2s. We find that iAT2s at ALI are more similar to primary AT2s than iAT2s cultured as spheres, and that differences are driven by primary AT2s' response to immune stimuli. We then test the capacity of iAT2s to respond to immune stimuli by infecting with SARSCoV-2. We find that iAT2s mount an epithelial-intrinsic interferon and inflammatory response to SARS-CoV-2 infection, and can serve as a platform for testing antiviral therapeutics. Finally, we demonstrate that iAT2s at ALI respond to cigarette smoke and electronic cigarette vapor, enabling the direct comparison of these common inhaled stimuli. Overall, we describe a novel disease modeling platform that will enable exploration of gene-environment interactions unique to inhaled exposures of the alveolar epithelium.

iProMix: A mixture model for studying the function of ACE2 based on bulk proteogenomic data.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over six million deaths in the ongoing COVID-19 pandemic. SARS-CoV-2 uses ACE2 protein to enter human cells, raising a pressing need to characterize proteins/pathways interacted with ACE2. Large-scale proteomic profiling technology is not mature at single-cell resolution to examine the protein activities in disease-relevant cell types. We propose iProMix, a novel statistical framework to identify epithelial-cell specific associations between ACE2 and other proteins/pathways with bulk proteomic data. iProMix decomposes the data and models cell-type-specific conditional joint distribution of proteins through a mixture model. It improves cell-type composition estimation from prior input, and utilizes a non-parametric inference framework to account for uncertainty of cell-type proportion estimates in hypothesis test. Simulations demonstrate iProMix has well-controlled false discovery rates and favorable powers in non-asymptotic settings. We apply iProMix to the proteomic data of 110 (tumor adjacent) normal lung tissue samples from the Clinical Proteomic Tumor Analysis Consortium lung adenocarcinoma study, and identify interferon α/γ response pathways as the most significant pathways associated with ACE2 protein abundances in epithelial cells. Strikingly, the association direction is sex-specific. This result casts light on the sex difference of COVID-19 incidences and outcomes, and motivates sex-specific evaluation for interferon therapies.

Characterizing Macrophages Diversity in COVID-19 Patients Using Deep Learning.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for coronavirus disease 2019 (COVID-19), has affected the lives of billions and killed millions of infected people. This virus has been demonstrated to have different outcomes among individuals, with some of them presenting a mild infection, while others present severe symptoms or even death. The identification of the molecular states related to the severity of a COVID-19 infection has become of the utmost importance to understanding the differences in critical immune response. In this study, we computationally processed a set of publicly available single-cell RNA-Seq (scRNA-Seq) data of 12 Bronchoalveolar Lavage Fluid (BALF) samples diagnosed as having a mild, severe, or no infection, and generated a high-quality dataset that consists of 63,734 cells, each with 23,916 genes. We extended the cell-type and sub-type composition identification and our analysis showed significant differences in cell-type composition in mild and severe groups compared to the normal. Importantly, inflammatory responses were dramatically elevated in the severe group, which was evidenced by the significant increase in macrophages, from 10.56% in the normal group to 20.97% in the mild group and 34.15% in the severe group. As an indicator of immune defense, populations of T cells accounted for 24.76% in the mild group and decreased to 7.35% in the severe group. To verify these findings, we developed several artificial neural networks (ANNs) and graph convolutional neural network (GCNN) models. We showed that the GCNN models reach a prediction accuracy of the infection of 91.16% using data from subtypes of macrophages. Overall, our study indicates significant differences in the gene expression profiles of inflammatory response and immune cells of severely infected patients.

iProMix: A mixture model for studying the function of ACE2 based on bulk proteogenomic data.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over six million deaths in the ongoing COVID-19 pandemic. SARS-CoV-2 uses ACE2 protein to enter human cells, raising a pressing need to characterize proteins/pathways interacted with ACE2. Large-scale proteomic profiling technology is not mature at single-cell resolution to examine the protein activities in disease-relevant cell types. We propose iProMix, a novel statistical framework to identify epithelial-cell specific associations between ACE2 and other proteins/pathways with bulk proteomic data. iProMix decomposes the data and models cell-type-specific conditional joint distribution of proteins through a mixture model. It improves cell-type composition estimation from prior input, and utilizes a non-parametric inference framework to account for uncertainty of cell-type proportion estimates in hypothesis test. Simulations demonstrate iProMix has well-controlled false discovery rates and favorable powers in non-asymptotic settings. We apply iProMix to the proteomic data of 110 (tumor adjacent) normal lung tissue samples from the Clinical Proteomic Tumor Analysis Consortium lung adenocarcinoma study, and identify interferon α/γ response pathways as the most significant pathways associated with ACE2 protein abundances in epithelial cells. Strikingly, the association direction is sex-specific. This result casts light on the sex difference of COVID-19 incidences and outcomes, and motivates sex-specific evaluation for interferon therapies.

Generation Of Macro-scale And Mature Lung Organoids Through Engineering Cell Microenvironment

Purpose/Objectives: <Most used lower respiratory tract models consist of cell monolayers which lack of tissue and organ level response and of in-vivo phenotype. Ex-vivo lung tissues have short viability and limited availability. Lung organoids, which recapitulates better the 3D cellular complex structures, architecture, and in-vivo function, fail to reach maturity even after 85 -185 days of culture. Therefore, these models have a limited use to study fetal lung diseases. Other lung models, consist of only one structure of the lower track, such as bronchial tubes or alveoli, but fail to recapitulate the whole organ structure. In this work, cell microenvironment was used to promote the self-organization of epithelial and mesenchymal cells into macro-structures, aiming to mimic the whole and adult lower respiratory tract model> Methodology: <Different parts of the microenvironment were considered to create a compliant matrix. Alginate-Gelatin hydrogels were used for 3D encapsulation of mesenchymal origin cells. This hydrogel provided a stiffness like the one on the lung. Base membrane zone proteins were used to induce the attachment and guidance of epithelial cells into 3D structures. The interactions between both cell types, further guided them into lung fate. The morphology of resulting organoids was analyzed using immunostaining and confocal microscopy, LSM710, with the purpose of evaluate polarization, protein markers, and different cell populations. Quantitative PCR was performed to evaluate and compare the expression of lung fate genes with traditional cell monocultures.> Results: <The engineered microenvironment and protocol development done in this work resulted in macro-scale structures, in which branching morphogenesis occurred at day 21. Different structures were identified in the organoid including bronchial tube, bronchioles, and alveoli. Polarization of the organoids was confirmed by visualization of E-cadherin, and ZO-1. Expression of Surfactant Protein B and C into the organoids confirmed the presence of alveolar type II cells, which are only present in the later development stage. Surfactant Protein B, Transmembrane protease, serine 2, TMPRSS-2, and Angiotensin-converting enzyme 2, ACE2 were found to be significantly higher expressed into the organoids in comparison with traditional epithelial cells monolayers.> Conclusion/Significance: <Growth factors are normally used to induce the fate of stem cells into lung organoids;however, these fail to reach maturity. Here, we developed a new methodology to induce the formation of the organoids based on the cell microenvironment. The resulting organoids require less time for development. The initial stage of adult cells can be modulated through culture conditions induce a 3D structure like the adult lung. As such, these organoids have the potential to be used for modeling adult diseases and to develop specific models from patient cells, which is one step forward to personalized medicine. SFTPB is one of the main proteins which facilitates the breathing process. Its high expression into our model may indicate that breathing occurs into our lung organoids. The higher expression of TMPRSS-2 and ACE2 into the organoids has a major significance in the field of virology since both proteins are the mainly entrance of SARS-CoV-2, and influenza H1N1.>.

IDENTIFYING A NOVEL SURFACTANT PROTEIN MUTATION IN A FAMILY WITH PULMONARY FIBROSIS

SESSION TITLE: Rare Genetic Mutations and Anatomical Variants SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 12:25 pm - 01:25 pm INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal disease affecting older adults that results in progressive scarring of the lung parenchyma. Familial IPF (FPF), defined by disease in two or more first-degree relatives, is estimated to occur in 2–20% of all IPF cases and can present with varying phenotypes which may be difficult to diagnose. Inherited gene variation as well as environmental factors predispose a patient to disease development. Additionally, rare genetic variants in the genes encoding surfactant A (SFTPA1, and SFTPA2) that affect alveolar stability and endoplasmic reticulum stress have been reported in less than 1% of FPF cases. Understanding these genetic variants is essential in the diagnosis and management of patients with FPF. CASE PRESENTATION: A 47-year-old Hispanic male with a history of COVID-19 one year ago (not requiring hospitalization) presented to the hospital for a two-day history of subjective fever and shortness of breath. He was hypoxic requiring oxygen via high flow nasal cannula. He was admitted four months ago for shortness of breath and treated for pneumonia. Since then, he has had chronic dyspnea with exertion. Computed tomography of the chest showed extensive ground glass opacities, worse in the right lung, with basilar and upper lobe honeycombing, and air bronchograms in the bilateral lower lobes. Family history was significant for a mother, maternal aunt, maternal grandfather, and maternal cousin who all died from pulmonary fibrosis. His maternal cousin was treated at our facility, in which genetic sequencing revealed a mutation in SFTPA2, c.697T>C. Our patient was found to have the same genetic mutation. DISCUSSION: The genetic basis of IPF remains poorly understood. Prior studies suggest only 20-30% of FPF cases harbor an identifiable causative genetic variant. Rare variants in two biologic pathways contribute to the known heritability of FPF including pathologic variants in surfactant related genes which cause improper protein trafficking leading to endoplasmic reticulum stress, defects in autophagy, and type II alveolar cell toxicity. SFTPA1 and SFTPA2 variants have been associated with FPF and lung adenocarcinoma in a small number of families and there are few reported cases. While currently the SFTPA2, c.697T>C mutation, previously reported by our group in 2016, is considered a variant of unknown significance, its occurrence in two relatives with serious progressive interstitial lung diseases suggests that it is indeed pathogenic. CONCLUSIONS: Gene sequencing should be considered for all patients with a family history of pulmonary fibrosis as identification of a rare genetic variant may offer guidance to diagnosis, prognostication, and risk stratification when considering lung transplantation as well as identify additional relatives who may be affected by IPF. Reference #1: Kropski JA, Young LR, Cogan JD, et al. Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017;195(11):1423-1428. doi:10.1164/rccm.201609-1820PP Reference #2: Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, DiMaio JM, Kinch LN, Grishin NV, Garcia CK. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009 Jan;84(1):52-9. doi: 10.1016/j.ajhg.2008.11.010. Epub 2008 Dec 18. PMID: 19100526;PMCID: PMC2668050. Reference #3: Pulmonary Fibrosis Due to a Novel Surfactant Protein Mutation R.A. Arciniegas Flores, I.A. Vital, K. Medepalli, D. DeMarzo, M.K. Glassberg Csete, R.A. Alvarez. https://doi.org/10.1164/ajrccm-conference.2019.199.1_Meetings.A5437 DISCLOSURES: No relevant relationships by Roger Alvarez No relevant relationships by Eduardo Lopez Gonzalez No relevant relationships by Anita Singh

CORRELATION OF C-REACTIVE PROTEIN (CRP) WITH ICU COVID-19 ARDS MORTALITY IN ADULTS

SESSION TITLE: Biological Markers in Patients with COVID-19 Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: C-REACTIVE PROTEIN (CRP) is an acute phase reactant produced by liver in response to cytokines especially Interleukin-6 (IL-6). CRP consists of five identical subunits arranged symmetrically around a central pore. CRP binds to phospholipid constituents of foreign pathogens and damaged cells to promote the elimination of pathogens and clearance of apoptotic cells. Covid 19 virus through the spike protein binds to Angiotensin Converting Enzyme 2 receptors of host target cells, particularly receptors of alveolar Type 2 epithelial cells. This reaction causes Cytokine storm syndrome with release of several cytokines including IL-6. The purpose of this study is to assess the significance of CRP levels in predicting mortality of Covid 19 infection induced Adult Respiratory Distress syndrome (ARDS) patients admitted in the Intensive Care Unit (ICU). METHODS: We retrospectively reviewed the records of covid 19 induced ARDS patients admitted to ICU between July 1st 2020 and June 30th 2021 in a community hospital. We collected the CRP level on admission and discharge (survived or deceased) during that admission. The discharge CRP level was subtracted from admission CRP level. The positive value was taken as elevated CRP level and negative value was taken as non-elevated CRP. RESULTS: A total of 484 covid patients were admitted at the ICU during that period. Of those, 228 patients had admission and discharge (survived or deceased) CRP lab value available. 177 patients survived with 33 (18.6%) had elevated CRP and 144 (81.4%) had non-elevated CRP levels. 51 patients deceased with 32 (62.7%) had elevated CRP and 10 (37.3%) had non-elevated CRP levels. The p-value is <.00001. CONCLUSIONS: Elevated CRP was associated with high ICU mortality in Covid 19 infected ARDS patients. CLINICAL IMPLICATIONS: CRP can be elevated initially due to Cytokine storm syndrome and later may be related to secondary infection especially with immunosuppressive treatment. Elevated CRP levels indicates higher inflammatory response which should prompt early appropriate intervention. DISCLOSURES: No relevant relationships by Ravi Chandran No relevant relationships by Pranav Vadhul

The Genetic Stability, Replication Kinetics and Cytopathogenicity of Recombinant Avian Coronaviruses with a T16A or an A26F Mutation within the E Protein Is Cell-Type Dependent.

The envelope (E) protein of the avian coronavirus infectious bronchitis virus (IBV) is a small-membrane protein present in two forms during infection: a monomer and a pentameric ion channel. Each form has an independent role during replication; the monomer disrupts the secretory pathway, and the pentamer facilitates virion production. The presence of a T16A or A26F mutation within E exclusively generates the pentameric or monomeric form, respectively. We generated two recombinant IBVs (rIBVs) based on the apathogenic molecular clone Beau-R, containing either a T16A or A26F mutation, denoted as BeauR-T16A and BeauR-A26F. The replication and genetic stability of the rIBVs were assessed in several different cell types, including primary and continuous cells, ex vivo tracheal organ cultures (TOCs) and in ovo. Different replication profiles were observed between cell cultures of different origins. BeauR-A26F replicated to a lower level than Beau-R in Vero cells and in ovo but not in DF1, primary chicken kidney (CK) cells or TOCs. Genetic stability and cytopathic effects were found to differ depending on the cell system. The effect of the T16A and A26F mutations appear to be cell-type dependent, which, therefore, highlights the importance of cell type in the investigation of the IBV E protein.

PI3Kgamma inhibition reduces inflammation and promotes survival in cancer and SARS-CoV-2

Solid tumors are characterized by extensive immune suppressive inflammation, vascular leak, fibrosis and organ damage. Similarly, SARS-CoV-2 infections induce aberrant pulmonary and systemic inflammation, vascular leak, coagulation, fibrosis and fatal organ damage. We previously demonstrated that macrophages in solid tumors strongly expressed phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinately controls granulocyte and monocyte trafficking to tumors as well as wound-healing-type macrophage transcription in cancer and fibrosis. We also observed that macrophages in COVID-19 lungs strongly expressed PI3Kγ. To identify therapeutic strategies to suppress COVID-19-associated inflammation, we characterized lung tissue of COVID19 patients using multiplex immunohistochemistry and tissue transcriptomics. Lungs of deceased patients exhibited substantial infiltration by neutrophils and wound-healing macrophages, fibrosis and alveolar type II cell depletion. In animal models of lung inflammation, bacterial infections, viral infection and SARS-CoV-2 infection, PI3Kγ deletion or inhibition with the cancer therapeutic IPI-549 (eganelisib) suppressed pulmonary and systemic inflammation, reduced lung damage, and promoted survival. These studies demonstrate the essential role of PI3Kγ in inflammatory diseases as well as cancer and support the use of PI3Kγ inhibitors such as eganelisib to suppress inflammation and promote survival in pulmonary infections like SARS-CoV-2 and cancer.

COVID 19 in a family with rare genetic disease of the nervous system

We present familial tuberous sclerosis (TS) case complicated by COVID-19. COVID-19 aggravates the course of TS and may lead to a fatal outcome. We review the role of mTORC1 (mechanistic/mammalian Target of Rapamycin Complex 1) in the development and functions of the nervous system and the pathogenesis of TS and COVID-19 with emphasis on the involvement of the brain and lungs. We observed that COVID-19 worsens the course of epilepsy in patients with TS. In TS patients, lymphangioleiomyomatosis may predispose to SARS-CoV-2 invasion into the respiratory system because of the increased expression of ACE2 and TMPRSS2 in type II pneumocytes and thus may worsen the prognosis. We also review the current data on the continuation/termination of everolimus administration in patients with TS associated with COVID-19.