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1.
European Surgical Research ; 63(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1893816

ABSTRACT

The proceedings contain 32 papers. The topics discussed include: molecular pathogenesis and prognostic stratification: acute myeloid leukemia;molecular pathogenesis and prognostic stratification of myelodysplastic syndromes;extracellular vesicles and their role in tumor microenvironment;new genomic, transcriptomic and cellular risk factors in multiple myeloma;drivers of progression in MPNS;SARS-COV2 coagulopathy: an intricated puzzle;role of the microenvironment in the pathogenesis of myelodysplastic syndromes;the tumor microenvironment in Hodgkin lymphoma: clinical implications;CRISPR/CAS9-based genome editing to model the anti-leukemia immune response and identify its molecular players;and deregulation of the transforming growth factor-B pathway in low-risk MDS patients SF3B1 mutated.

2.
JCI Insight ; 7(11)2022 06 08.
Article in English | MEDLINE | ID: covidwho-1816975

ABSTRACT

Secondary infections are frequent complications of viral respiratory infections, but the potential consequence of SARS-CoV-2 coinfection with common pulmonary pathogens is poorly understood. We report that coinfection of human ACE2-transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following coinfection were associated with alveolar macrophage depletion, and treatment with murine GM-CSF reduced numbers of lung bacteria and pathology and partially protected from death. However, therapeutic targeting of IFNs, an approach that is effective against influenza coinfections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent coinfection. The results indicate that when seasonal respiratory infections return to prepandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population.


Subject(s)
COVID-19 , Coinfection , Animals , COVID-19/prevention & control , Mice , Mice, Transgenic , SARS-CoV-2 , Streptococcus pneumoniae , Vaccination
3.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-331167

ABSTRACT

Background: Certain riboviruses can cause severe pulmonary complications leading to death in some infected patients. We propose that DNA damage induced-apoptosis accelerates viral release, triggered by depletion of host RNA binding proteins (RBPs) from nuclear RNA bound to replicating viral sequences. Methods: Information theory-based analysis of interactions between RBPs and individual sequences in the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), Influenza A (H3N2), HIV-1, and Dengue genomes identifies strong RBP binding sites in these viral genomes. Replication and expression of viral sequences is expected to increasingly sequester RBPs - SRSF1 and RNPS1. Ordinarily, RBPs bound to nascent host transcripts prevents their annealing to complementary DNA. Their depletion induces destabilizing R-loops. Chromosomal breakage occurs when an excess of unresolved R-loops collide with incoming replication forks, overwhelming the DNA repair machinery. We estimated stoichiometry of inhibition of RBPs in host nuclear RNA by counting competing binding sites in replicating viral genomes and host RNA. Results: Host RBP binding sites are frequent and conserved among different strains of RNA viral genomes. Similar binding motifs of SRSF1 and RNPS1 explain why DNA damage resulting from SRSF1 depletion is complemented by expression of RNPS1. Clustering of strong RBP binding sites coincides with the distribution of RNA-DNA hybridization sites across the genome. SARS-CoV-2 replication is estimated to require 32.5-41.8 hours to effectively compete for binding of an equal proportion of SRSF1 binding sites in host encoded nuclear RNAs. Significant changes in expression of transcripts encoding DNA repair and apoptotic proteins were found in an analysis of influenza A and Dengue-infected cells in some individuals. Conclusions: R-loop-induced apoptosis indirectly resulting from viral replication could release significant quantities of membrane-associated virions into neighboring alveoli. These could infect adjacent pneumocytes and other tissues, rapidly compromising lung function, causing multiorgan system failure and other described symptoms.

4.
Arch Oral Biol ; 136: 105374, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1676407

ABSTRACT

OBJECTIVE: This living systematic review aims to integrate the morphological and tissue-based molecular characterization of oral lesions occurring in individuals infected by COVID-19 (OLICs). MATERIALS AND DESIGN: This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Web of Science, Scopus, Ovid, Embase, and LILACS were searched to identify reports on OLICs with morphological and/or tissue-based molecular data. RESULTS: Four studies reporting five cases were included. Three patients were male, and the mean age of the individuals was 47.6 years. The most reported anatomical location was the palate (n = 4), whereas ulcers were the most frequent clinical presentation (n = 3). Histopathologically, all cases revealed cell vacuolization and exocytosis in the epithelial layer. In the mesenchymal layer, inflammatory cell infiltrate and thrombi/microvascular thrombosis were observed in three cases. Immunohistochemical reactions were performed in two cases. Both cases were negative for HHV-1, HHV-2, and CMV. One case revealed positivity for SARS-CoV-2 spike protein. No other molecular tests were found for the characterization of OLIC. CONCLUSIONS: The pathological characteristics of OLICs are still unspecific. However, with the ongoing COVID-19 pandemic and well-documented new cases, whether OLICs are due to coinfections or has a primary origin can be determined.


Subject(s)
COVID-19 , Humans , Male , Middle Aged , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
5.
Circulation ; 144(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1632416

ABSTRACT

Cardiac microthrombi are postulated to underlie cardiac injury in critical COVID-19. To determine pathogenic mechanism(s) of cardiac injury in fatal COVID-19, we conducted a single-center prospective cohort study of 69 consecutive COVID-19 decedents. Microthrombi was the most commonly detected acute cardiac histopathologic feature (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with inhospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi (ESR, Pnonlinearity 0.015, Passociation=0.008;CRP per 20mg/L increase, OR 1.17, 95%CI 1.00-1.36). Using single nuclei RNA-sequence analysis, we discovered an enrichment of prothrombotic, anti-fibrinolytic, and extracellular matrix signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts, compared with microthrombi-negative COVID-19 hearts and non-COVID-19 donor hearts. Our cumulative findings identify these specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.

6.
JCI Insight ; 7(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1571524

ABSTRACT

Acute cardiac injury is prevalent in critical COVID-19 and associated with increased mortality. Its etiology remains debated, as initially presumed causes - myocarditis and cardiac necrosis - have proved uncommon. To elucidate the pathophysiology of COVID-19-associated cardiac injury, we conducted a prospective study of the first 69 consecutive COVID-19 decedents at CUIMC in New York City. Of 6 acute cardiac histopathologic features, presence of microthrombi was the most commonly detected among our cohort. We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with in-hospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak erythrocyte sedimentation rate and C-reactive protein were independently associated with increased odds of microthrombi, supporting an immunothrombotic etiology. Using single-nuclei RNA-sequencing analysis on 3 patients with and 4 patients without cardiac microthrombi, we discovered an enrichment of prothrombotic/antifibrinolytic, extracellular matrix remodeling, and immune-potentiating signaling among cardiac fibroblasts in microthrombi-positive, relative to microthrombi-negative, COVID-19 hearts. Non-COVID-19, nonfailing hearts were used as reference controls. Our study identifies a specific transcriptomic signature in cardiac fibroblasts as a salient feature of microthrombi-positive COVID-19 hearts. Our findings warrant further mechanistic study as cardiac fibroblasts may represent a potential therapeutic target for COVID-19-associated cardiac microthrombi.


Subject(s)
COVID-19 , Heart Injuries , RNA-Seq , SARS-CoV-2/metabolism , Thrombosis , Adult , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/metabolism , COVID-19/pathology , Female , Heart Injuries/genetics , Heart Injuries/metabolism , Heart Injuries/pathology , Humans , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology , Prospective Studies , Thrombosis/genetics , Thrombosis/metabolism , Thrombosis/pathology
7.
JCI Insight ; 6(24)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1518199

ABSTRACT

Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.


Subject(s)
Acute Kidney Injury/urine , COVID-19/urine , Kidney Tubules, Proximal/virology , Kidney/virology , Organoids/virology , SARS-CoV-2/pathogenicity , Acute Kidney Injury/etiology , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Animals , Apoptosis , Bowman Capsule/cytology , Bowman Capsule/virology , COVID-19/complications , Chlorocebus aethiops , Female , Gene Knockout Techniques , Hospital Mortality , Hospitalization , Humans , Kidney/metabolism , Kidney/pathology , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Male , Middle Aged , Organoids/metabolism , Podocytes/virology , Polycystic Kidney Diseases , Proteome , Receptors, Coronavirus/genetics , Reproducibility of Results , Transcriptome , Vero Cells , Viral Tropism , Virus Replication
8.
JCI Insight ; 6(21)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1506181

ABSTRACT

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.


Subject(s)
Aging , COVID-19/metabolism , Chitinase-3-Like Protein 1/metabolism , Aging/drug effects , Aminoglycosides/pharmacology , Aminoglycosides/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Cell Line, Tumor , Chitinase-3-Like Protein 1/antagonists & inhibitors , HEK293 Cells , Humans , SARS-CoV-2/physiology
9.
Diagnostics (Basel) ; 11(2)2021 Feb 18.
Article in English | MEDLINE | ID: covidwho-1457562

ABSTRACT

Current pathology practice is being shaped by the increasing complexity of modern medicine, in particular of precision oncology, and major technological advances. In the "next-generation technologies era", the pathologist has become the person responsible for the integration and interpretation of morphologic and molecular information and for the delivery of critical answers to diagnostic, prognostic and predictive queries, acquiring a prominent position in the molecular tumor boards.

10.
JCI Insight ; 5(19)2020 10 02.
Article in English | MEDLINE | ID: covidwho-1388620

ABSTRACT

The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.


Subject(s)
Cause of Death , Coronavirus Infections/pathology , Disease Progression , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/pathology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/physiopathology , Disease Models, Animal , Female , Humans , Lung/pathology , Male , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/physiopathology , Severe Acute Respiratory Syndrome/physiopathology , Severity of Illness Index , Survival Rate , Virus Replication/genetics
11.
J Dev Biol ; 9(3)2021 Aug 25.
Article in English | MEDLINE | ID: covidwho-1374442

ABSTRACT

A subset of placentas from pregnant women having the SARS-CoV-2 infection have been found to be infected with the coronavirus using molecular pathology methods including immunohistochemistry and RNA in situ hybridization. These infected placentas can demonstrate several unusual findings which occur together-chronic histiocytic intervillositis, trophoblast necrosis and positive staining of the syncytiotrophoblast for SARS-CoV-2. They frequently also have increased fibrin deposition, which can be massive in some cases. Syncytiotrophoblast is the most frequent fetal-derived cell type to be positive for SARS-CoV-2. It has recently been shown that in a small number of infected placentas, villous stromal macrophages, termed Hofbauer cells, and villous capillary endothelial cells can also stain positive for SARS-CoV-2. This report describes a placenta from a pregnant woman with SARS-CoV-2 that had chronic histiocytic intervillositis, trophoblast necrosis, increased fibrin deposition and positive staining of the syncytiotrophoblast for SARS-CoV-2. In addition, molecular pathology testing including RNAscope and immunohistochemistry for SARS-CoV-2 and double-staining immunohistochemistry using antibodies to E-cadherin and GATA3 revealed that cytotrophoblast cells stained intensely for SARS-CoV-2. All of the cytotrophoblast cells that demonstrated positive staining for SARS-CoV-2 were in direct physical contact with overlying syncytiotrophoblast that also stained positive for the virus. The pattern of cytotrophoblast staining for SARS-CoV-2 was patchy, and there were chorionic villi having diffuse positive staining of the syncytiotrophoblast for SARS-CoV-2, but without staining of cytotrophoblast. This first detailed description of cytotrophoblast involvement by SARS-CoV-2 adds another fetal cell type from infected placentas that demonstrate viral staining.

12.
J Clin Invest ; 131(19)2021 10 01.
Article in English | MEDLINE | ID: covidwho-1371926

ABSTRACT

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.


Subject(s)
COVID-19/blood , COVID-19/mortality , Group II Phospholipases A2/blood , SARS-CoV-2/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Child , Disease-Free Survival , Female , Humans , Male , Middle Aged , Severity of Illness Index , Survival Rate
13.
J Racial Ethn Health Disparities ; 2021 Jul 28.
Article in English | MEDLINE | ID: covidwho-1330444

ABSTRACT

BACKGROUND AND AIMS: It has been documented that African Americans have been significantly affected by COVID-19 infection due to systemic societal factors, which may lead to increases in comorbid medical history and subsequently vulnerability to having higher viral loads as measured by the cycle threshold/number (CT/CN) values by reverse transcriptase polymerase chain reaction (RT-PCR). Differences in CT/CN values by ethnicity and comorbid medical history could play an important role in public health research, particularly in elucidating the reasons for differential public health outcomes by ethnicity, as viral loads are known to correlate with disease severity. However, there is a gap in the literature regarding CT/CN values by ethnicity and comorbid medical history. Therefore, this study seeks to address this literature gap and its important implication for public health research. METHODS: A retrospective review of all SARS-CoV-2 RT-PCR tests collected at the regional Veterans Administration Medical Center (VAMC) serving the Philadelphia area from March 17, 2020, to May 20, 2020, was performed to collect demographic information such as race, gender, and age. In addition, comorbid medical conditions, clinical course, and CT/CN values were obtained for the positive cases. RESULTS: There was a total of 1524 patients tested for SARS-CoV-2. A total of 713/1524 patients (46.8%) were African American. A total of 187/1524 patients (12%) had tested positive for SARS-CoV-2 from which 139/187 (74%) were African American. African American patients required more intensive unit care. Both African Americans and other ethnicities had similar rates of comorbid medical conditions. On comparison of the ethnic groups, there were lower viral loads in African Americans on admission, though the difference was not statistically significant. CONCLUSION: African American Veterans tested positive at higher rates and require more ICU care, despite similar rates of comorbid illness and viral loads.

14.
J Clin Invest ; 131(13)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1304352

ABSTRACT

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.


Subject(s)
COVID-19/virology , Host Microbial Interactions , Nasal Mucosa/virology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/pathology , COVID-19/physiopathology , Cell Differentiation , Cilia/pathology , Cilia/physiology , Cilia/virology , Furin/genetics , Furin/metabolism , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Macaca , Models, Biological , Nasal Mucosa/pathology , Nasal Mucosa/physiopathology , Pandemics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Seq , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Stem Cells/pathology , Stem Cells/virology , Virus Internalization , Virus Replication/genetics , Virus Replication/physiology
15.
J Clin Invest ; 131(6)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1133409

ABSTRACT

The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pathophysiology of the placenta and its impact on pregnancy outcome has not yet been fully elucidated. Here, we present a comprehensive clinical, morphological, and molecular analysis of placental tissues from pregnant women with and without SARS-CoV-2 infection. SARS-CoV-2 could be detected in half of placental tissues from SARS-CoV-2-positive women. The presence of the virus was not associated with any distinctive pathological, maternal, or neonatal outcome features. SARS-CoV-2 tissue load was low in all but one patient who exhibited severe placental damage leading to neonatal neurological manifestations. The placental transcriptional response induced by high viral load of SARS-CoV-2 showed an immunopathology phenotype similar to autopsy lung tissues from patients with severe coronavirus disease 2019. This finding contrasted with the lack of inflammatory response in placental tissues from SARS-CoV-2-positive women with low viral tissue load and from SARS-CoV-2-negative women. Importantly, no evidence of vertical transmission of SARS-CoV-2 was found in any newborns, suggesting that the placenta may be an effective maternal-neonatal barrier against the virus even in the presence of severe infection. Our observations suggest that severe placental damage induced by the virus may be detrimental for the neonate independently of vertical transmission.


Subject(s)
COVID-19/complications , COVID-19/virology , Placenta Diseases/virology , Pregnancy Complications, Infectious/virology , Adult , COVID-19/transmission , Cohort Studies , Female , Gene Expression Profiling , Humans , Infant, Newborn , Infectious Disease Transmission, Vertical , Pandemics , Placenta/pathology , Placenta/virology , Placenta Diseases/genetics , Placenta Diseases/pathology , Pregnancy , Pregnancy Complications, Infectious/genetics , Pregnancy Complications, Infectious/pathology , Pregnancy Outcome , RNA, Viral/genetics , RNA, Viral/isolation & purification , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , Young Adult
16.
J Clin Invest ; 130(12): 6728-6738, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-972513

ABSTRACT

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship among anti-spike ectodomain (anti-ECD), anti-receptor-binding domain (anti-RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by 2 in vitro assays using convalescent plasma samples from 68 patients with COVID-19. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titers. The probability of a VN titer of ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was ≥80% when anti-RBD or anti-ECD titers were ≥1:1350. Of all donors, 37% lacked VN titers of ≥160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of ≥1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers of ≥1:160, and all of them had anti-RBD titers of ≥1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of ≥1:1350 may provide critical information about protection against COVID-19 disease.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Immunoglobulin G , SARS-CoV-2 , Adolescent , Adult , Aged , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/blood , Antibodies, Viral/administration & dosage , Antibodies, Viral/blood , Female , Humans , Immunization, Passive , Immunoglobulin G/administration & dosage , Immunoglobulin G/blood , Male , Middle Aged
17.
Cytopathology ; 32(3): 299-303, 2021 May.
Article in English | MEDLINE | ID: covidwho-962983

ABSTRACT

Since its first identification in China at the end of 2019, severe acute respiratory syndrome coronavirus 2 has rapidly spread all over the world, becoming an international healthcare emergency. In the era of coronavirus disease-2019 (COVID-19), several aspects of normal life, including those related to the medical activities, have been radically changed. Extraordinary measures have been adopted by different nations to cope with the rapid diffusion of COVID-19 all over the world. In hospitals, careful attention has been paid to manage infected patients with a possible detrimental effect for patients affected by other diseases. As with other medical fields, cytopathology laboratories have also drastically modified their activities to cope with the COVID-19 healthcare emergency. Here, the main effects of COVID-19 pandemic on the routine practice of cytopathology are summarised, focusing on the prioritisation policy adopted by cytopathologists worldwide.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , COVID-19/prevention & control , SARS-CoV-2 , Pandemics
18.
Lab Med ; 52(2): e39-e45, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-939575

ABSTRACT

OBJECTIVE: With the COVID-19 pandemic, there have been supply challenges necessitating that laboratories must prepare their own viral transport medium (VTM), which provides stability for clinical specimens for diagnostic viral testing. METHODS: Within a veteran affairs medical center clinical laboratory, VTM was prepared with a Hanks Balanced Salt Solution (HBSS) 500 mL bottle with phenol red, sterile heat-inactivated fetal bovine serum (FBS), gentamicin sulfate (50 mg/mL), and amphotericin B (250 µg/mL). An antimicrobial mixture was made of 50 mL each of amphotericin B and gentamicin sulfate. Ten mL of FBS and 2 mL of the antimicrobial mixture were mixed into the HBSS bottle, from which 3 mL aliquots were made. Sterility and efficacy check were assessed. These preparations were conducted at our VAMC's clinical laboratory to assure adequate VTM supply during the COVID-19 shortage. RESULTS: The VTM was successfully prepared in-house, supporting uninterrupted testing for the facility and other affiliated medical facilities/centers and community living centers. CONCLUSION: This quality assurance/improvement report represents the first published manuscript on feasible VTM preparation exclusively within a clinical microbiology laboratory during the COVID-19 pandemic.


Subject(s)
COVID-19 , Culture Media , SARS-CoV-2 , Humans , Quality Control , Specimen Handling
19.
Respir Med ; 176: 106239, 2021 01.
Article in English | MEDLINE | ID: covidwho-933468

ABSTRACT

COVID-19 has quickly reached pandemic levels since it was first reported in December 2019. The virus responsible for the disease, named SARS-CoV-2, is enveloped positive-stranded RNA viruses. During its replication in the cytoplasm of host cells, the viral genome is transcribed into proteins, such as the structural protein spike domain S1, which is responsible for binding to the cell receptor of the host cells. Infected patients have initially flu-like symptoms, rapidly evolving to severe acute lung injury, known as acute respiratory distress syndrome (ARDS). ARDS is characterized by an acute and diffuse inflammatory damage into the alveolar-capillary barrier associated with a vascular permeability increase and reduced compliance, compromising gas exchange and causing hypoxemia. Histopathologically, this condition is known as diffuse alveolar damage which consists of permanent damage to the alveoli epithelial cells and capillary endothelial cells, with consequent hyaline membrane formation and eventually intracapillary thrombosis. All of these mechanisms associated with COVID-19 involve the phenotypic expression from different proteins transcription modulated by viral infection in specific pulmonary microenvironments. Therefore, this knowledge is fundamentally important for a better pathophysiological understanding and identification of the main molecular pathways associated with the disease evolution. Evidently, clinical findings, signs and symptoms of a patient are the phenotypic expression of these pathophysiological and molecular mechanisms of SARS-CoV-2 infection. Therefore, no findings alone, whether molecular, clinical, radiological or pathological axis are sufficient for an accurate diagnosis. However, their intersection and/or correlation are extremely critical for clinicians establish the diagnosis and new treatment perspectives.


Subject(s)
COVID-19/complications , COVID-19/pathology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Humans
20.
J Clin Invest ; 130(9): 4947-4953, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-611525

ABSTRACT

BACKGROUNDThe effects of the novel coronavirus disease 2019 (COVID-19) in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic COVID-19 complicated by severe preeclampsia and placental abruption.METHODSWe analyzed the placenta for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through molecular and immunohistochemical assays and by and electron microscopy and measured the maternal antibody response in the blood to this infection.RESULTSSARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the materno-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for the vasculopathy typically associated with preeclampsia.CONCLUSIONThis case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with COVID-19.FUNDINGBeatrice Kleinberg Neuwirth Fund and Fast Grant Emergent Ventures funding from the Mercatus Center at George Mason University. The funding bodies did not have roles in the design of the study or data collection, analysis, and interpretation and played no role in writing the manuscript.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Placenta/pathology , Placenta/virology , Pneumonia, Viral/complications , Pregnancy Complications, Infectious/etiology , Pregnancy Complications, Infectious/virology , Abortion, Therapeutic , Abruptio Placentae/etiology , Abruptio Placentae/pathology , Abruptio Placentae/virology , Adult , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Microscopy, Electron, Transmission , Pandemics , Phylogeny , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pre-Eclampsia/etiology , Pre-Eclampsia/pathology , Pre-Eclampsia/virology , Pregnancy , Pregnancy Complications, Infectious/pathology , Pregnancy Trimester, Second , RNA, Viral/genetics , RNA, Viral/isolation & purification , SARS-CoV-2 , Viral Load
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