Corpus overview


MeSH Disease

Human Phenotype


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    A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis MESHD genes' interactions points to Neutrophil Extracellular Traps as mediators of thrombosis MESHD in COVID-19

    Authors: Jun Ding; David Earl Hostallero; Mohamed Reda El Khili; Gregory J Fonseca; Simon Milette; Nuzha Noorah; Myriam Guay-Belzile; Jonathan Spicer; Noriko Daneshtalab; Martin Sirois; Karine Tremblay; Amin Emad; Simon Rousseau

    doi:10.1101/2020.07.01.20144121 Date: 2020-07-02 Source: medRxiv

    Abnormal coagulation and an increased risk of thrombosis MESHD are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis MESHD (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis MESHD. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism MESHD thromboembolism HP to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis MESHD in severe COVID-19 in children TRANS and adults TRANS. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic MESHD and metabolic disorders.

    Cytokine release syndrome MESHD is not usually caused by secondary hemophagocytic lymphohistiocytosis MESHD in a cohort of 19 critically ill COVID-19 patients

    Authors: Georg Lorenz; Philipp Moog; Quirin Bachmann; Paul La Rosee; Heike Schneider; Michaela Schlegl; Christoph Spinner; Uwe Heemann; Roland M Schmid; Hana Algül; Tobias Lahmer; Wolfgang Huber; Christoph Schmaderer

    doi:10.21203/ Date: 2020-05-27 Source: ResearchSquare

    Background: Severe COVID-19 associated respiratory failure HP, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis MESHD (sHLH) or cytokine release syndrome MESHD (CRS) with features of macrophage activation syndrome MESHD might drive severe disease MESHD trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach.Methods: Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death MESHD at time of analysis.Results: The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever MESHD fever HP and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio>3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n=8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n=9).Conclusion: Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

    Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease MESHD with thrombotic microangiopathy MESHD and aberrant immune response. The Mount Sinai COVID-19 autopsy experience

    Authors: Clare Bryce; Zachary Grimes; Elisabet Pujadas; Sadhna Ahuja; Mary Beth Beasley; Randy Albrecht; Tahyna Hernandez; Aryeh Stock; Zhen Zhao; Mohamed Al Rasheed; Joyce Chen; Li Li; Diane Wang; Adriana Corben; Kenneth Haines; William Westra; Melissa Umphlett; Ronald E Gordon; Jason Reidy; Bruce Petersen; Fadi Salem; MariaIsabel Fiel; Siraj M El Jamal; Nadejda M Tsankova; Jane Houldsworth; Zarmeen Mussa; Wen-Chun Liu; Brandon Veremis; Emilia Sordillo; Melissa Gitman; Michael Nowak; Rachel Brody; Noam Harpaz; Miriam Merad; Sacha Gnjatic; Ryan Donnelly; Patricia Seigler; Calvin Keys; Jennifer Cameron; Isaiah Moultrie; Kae-Lynn Washington; Jacquelyn Treatman; Robert Sebra; Jeffrey Jhang; Adolfo Firpo; John Lednicky; Alberto Paniz-Mondolfi; Carlos Cordon-Cardo; Mary Fowkes

    doi:10.1101/2020.05.18.20099960 Date: 2020-05-22 Source: medRxiv

    BACKGROUND Severe Acute Respiratory Syndrome MESHD Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome MESHD COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease MESHD process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission TRANS electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNF. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis HP and a secondary hemophagocytic lymphohistiocytosis MESHD-like syndrome MESHD in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease MESHD, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy MESHD, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome MESHD, with hemophagocytosis HP and a hemophagocytic lymphohistiocytosis MESHD-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.

    SARS-CoV-2 Infection MESHD Associated Hemophagocytic Lymphohistiocytosis MESHD: An autopsy series with clinical and laboratory correlation.

    Authors: Andrey Prilutskiy; Michael Kritselis; Artem Shevtsov; Ilyas Yambayev; Charitha Vadlamudi; Qing Zhao; Yachana Kataria; Shayna Sarosiek; Adam Lerner; John Mark Sloan; Karen Quillen; Eric Burks

    doi:10.1101/2020.05.07.20094888 Date: 2020-05-12 Source: medRxiv

    Background: A subset of COVID-19 patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis MESHD (HLH) have not been reported. Pathologic studies to date have largely focused on the pulmonary finding of diffuse alveolar damage (DAD). To this aim, we study the reticuloendothelial organs of four consecutive patients dying of COVID-19 and correlate with clinical and laboratory parameters to detect HLH. Methods: Autopsies restricted to chest and abdomen were performed on four patients who succumbed to COVID-19. Spleen, liver, and multiple pulmonary hilar/mediastinal lymph nodes were sampled in all cases. Bone marrow was obtained by rib squeeze in a subset of cases. Routine H&E staining as well as immunohistochemical staining for CD163 was performed to detect hemophagocytosis HP. Clinical and laboratory results from pre-mortem blood SERO samples were used to calculate H-scores. Findings: All four cases demonstrated DAD within the lungs. Three of the four cases had histologic evidence of hemophagocytosis HP within pulmonary hilar/mediastinal lymph nodes. One case showed hemophagocytosis HP in the spleen but none showed hemophagocytosis HP in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis HP observed. One patient showed diagnostic features of HLH with an H-score of 217 while a second patient was likely HLH with a partial H-score of 145 due to missing triglyceride level. Both patients exhibited high fever MESHD fever HP and early onset rise in serum SERO ferritin; however, neither bicytopenia, pancytopenia MESHD pancytopenia HP, nor hypofibrinogenemia HP were observed in either. The remaining two patients had H-scores of 131 and 96. Interpretation: This is the first report of SARS-CoV-2 associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.

    Iron metabolism and lymphocyte characterisation during Covid-19 infection MESHD in ICU patients: an observational cohort study.

    Authors: Giuliano Bolondi; Emanuele Russo; Emiliano Gamberini; Alessandro Circelli; Manlio Cosimo Claudio Meca; Etrusca Brogi; Lorenzo Viola; Luca Bissoni; Venerino Poletti; Vanni Agnoletti

    doi:10.21203/ Date: 2020-04-30 Source: ResearchSquare

    Background: Iron metabolism and immune response to SARS-CoV-2 have not been described yet in intensive care patients, although they are likely involved in Covid-19 pathogenesis.Methods: We performed an observational study during the peak of pandemic in our intensive care unit, dosing D-dimer, C-reactive protein, Troponin T, Lactate Dehydrogenase, Ferritin, Serum SERO iron, Transferrin, Transferrin Saturation, Transferrin Soluble Receptor, Lymphocyte count and NK, CD3, CD4, CD8, B subgroups of 31 patients during the first two weeks of their ICU stay. Correlation with mortality and severity at the time of admission was tested with Spearman coefficient and Mann-Whitney test. Trends over time were tested with Kruskall-Wallis analysis.Results: Lymphopenia MESHD Lymphopenia HP is severe and constant, with a nadir on day 2 of ICU stay (median 0.555 109/L; interquartile range (IQR) 0.450 109/L); all lymphocytic subgroups are dramatically reduced in critically ill patients, while CD4/CD8 ratio remains normal. Neither Ferritin nor lymphocyte count follow significant trends in ICU patients. Transferrin Saturation is extremely reduced at ICU admission (median 9%; IQR 7%), then significantly increases at day 3 to 6 (median 33%, IQR 26.5%, p-value 0.026). The same trend is observed with serum SERO iron levels (median 25.5 µg/L, IQR 69 µg/L at admission; median 73 µg/L, IQR 56 µg/L on day 3 to 6) without reaching statistical significance. Hyperferritinemia is constant during intensive care stay: however, its dosage might be helpful in individuating patients developing hemophagocytic lymphohistiocytosis MESHD. D-dimer is elevated and progressively increases from admission (median 1319 µg/L; IQR 1285 µg/L) to day 3 to 6 (median 6820 µg/L; IQR 6619 µg/L), despite not reaching significant results. We describe trends of all the above mentioned parameters during ICU stay.Conclusions: The description of iron metabolism and lymphocyte count in Covid-19 patients admitted to the Intensive Care Unit provided with this paper might allow a wider understanding of SARS-CoV-2 pathophysiology.

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MeSH Disease
Human Phenotype

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