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Journal ArticleDOI

Serum Protein Profiling Reveals a Specific Upregulation of the Immunomodulatory Protein Progranulin in Coronavirus Disease 2019.

TL;DR: The data from this registry reveals that GRN is specifically upregulated in SARS-CoV-2 positive patients while interleukin-6 may serve as marker for disease severity in COVID-19.
Abstract: BACKGROUND: Severe courses of COVID-19 are associated with elevated levels of interleukin 6. However, there is a growing body of evidence pointing to a broad and more complex disorder of pro-inflammatory and anti-viral responses with disturbed interferon signaling in COVID-19. METHODS: In this prospective single-center registry, we included SARS-CoV-2 positive patients and patients with similar symptoms and severity of disease but negative for SARS-CoV-2 admitted to the emergency department and compared their serum protein expression profiles. RESULTS: Interleukin-6 abundance was similar in SARS-CoV-2 positive patients (n = 24) compared to SARS-CoV-2 negative control (n = 61). In contrast, we observed a specific upregulation of the immunomodulatory protein progranulin (GRN). High GRN abundance was associated with adverse outcomes and increased expression of interleukin-6 in COVID-19. CONCLUSION: The data from this registry reveals that GRN is specifically upregulated in SARS-CoV-2 positive patients while interleukin-6 may serve as marker for disease severity. The potential of GRN as a biomarker and a possible impact of increased GRN expression on interferon signaling, virus elimination, and virus-induced lung tissue damage in COVID-19 should be further explored.

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Citations
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01 Jan 2020
TL;DR: Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future.
Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

4,408 citations

Journal ArticleDOI
TL;DR: In this article , the authors delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thromboembolic events in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine Thrombosis with throm bocytopenia syndrome.
Abstract: Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.

136 citations

Journal ArticleDOI
TL;DR: In this article, the authors used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected recovered (hospital discharge), nonsevere (hospitalized), and severe [at the intensive care unit (ICU)] cases with increasing systemic inflammation in comparison with healthy individuals sampled prior to the COVID-19 pandemic.
Abstract: The COVID-19 pandemic caused by SARS-CoV-2 challenges the understanding of factors affecting disease progression and severity. The identification of prognostic biomarkers and physiological processes associated with disease symptoms is relevant for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic. To address this challenge, in this study, we used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected recovered (hospital discharge), nonsevere (hospitalized), and severe [at the intensive care unit (ICU)] cases with increasing systemic inflammation in comparison with healthy individuals sampled prior to the COVID-19 pandemic. The results showed significantly dysregulated proteins and associated biological processes and disorders associated to COVID-19. These results corroborated previous findings in COVID-19 studies and highlighted how the representation of dysregulated serum proteins and associated BPs increases with COVID-19 disease symptomatology from asymptomatic to severe cases. The analysis was then focused on novel disease processes and biomarkers that were correlated with disease symptomatology. To contribute to translational medicine, results corroborated the predictive value of selected immune-related biomarkers for disease recovery [Selenoprotein P (SELENOP) and Serum paraoxonase/arylesterase 1 (PON1)], severity [Carboxypeptidase B2 (CBP2)], and symptomatology [Pregnancy zone protein (PZP)] using protein-specific ELISA tests. Our results contributed to the characterization of SARS-CoV-2-host molecular interactions with potential contributions to the monitoring and control of this pandemic by using immune-related biomarkers associated with disease symptomatology.

22 citations

Journal ArticleDOI
TL;DR: Based on the close integration of their proteomic analysis with clinical data, they propose that COVID-19 is associated with prolonged disorders in cholesterol metabolism and myocardium, even in the recovery stage as discussed by the authors.
Abstract: The COVID-19 pandemic has become a worldwide health crisis. So far, most studies have focused on the epidemiology and pathogenesis of this infectious disease. Little attention has been given to the disease sequelae in patients recovering from COVID-19, and nothing is known about the mechanisms underlying these sequelae. Herein, we profiled the serum proteome of a cohort of COVID-19 patients in the disease onset and recovery stages. Based on the close integration of our proteomic analysis with clinical data, we propose that COVID-19 is associated with prolonged disorders in cholesterol metabolism and myocardium, even in the recovery stage. We identify potential biomarkers for these disorders. Moreover, severely affected patients presented more serious disturbances in these pathways. Our findings potentially support clinical decision-making to improve the prognosis and treatment of patients.

12 citations

References
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Journal ArticleDOI
TL;DR: Wang et al. as discussed by the authors used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death, including older age, high SOFA score and d-dimer greater than 1 μg/mL.

20,189 citations

Journal ArticleDOI
TL;DR: This study conducted a retrospective multicenter study of 68 death cases and 82 discharged cases with laboratory-confirmed infection of SARS-CoV-2 and confirmed that some patients died of fulminant myocarditis, which is characterized by a rapid progress and a severe state of illness.
Abstract: Dear Editor, The rapid emergence of COVID-19 in Wuhan city, Hubei Province, China, has resulted in thousands of deaths [1]. Many infected patients, however, presented mild flu-like symptoms and quickly recover [2]. To effectively prioritize resources for patients with the highest risk, we identified clinical predictors of mild and severe patient outcomes. Using the database of Jin Yin-tan Hospital and Tongji Hospital, we conducted a retrospective multicenter study of 68 death cases (68/150, 45%) and 82 discharged cases (82/150, 55%) with laboratory-confirmed infection of SARS-CoV-2. Patients met the discharge criteria if they had no fever for at least 3 days, significantly improved respiratory function, and had negative SARS-CoV-2 laboratory test results twice in succession. Case data included demographics, clinical characteristics, laboratory results, treatment options and outcomes. For statistical analysis, we represented continuous measurements as means (SDs) or as medians (IQRs) which compared with Student’s t test or the Mann–Whitney–Wilcoxon test. Categorical variables were expressed as numbers (%) and compared by the χ2 test or Fisher’s exact test. The distribution of the enrolled patients’ age is shown in Fig. 1a. There was a significant difference in age between the death group and the discharge group (p < 0.001) but no difference in the sex ratio (p = 0.43). A total of 63% (43/68) of patients in the death group and 41% (34/82) in the discharge group had underlying diseases (p = 0.0069). It should be noted that patients with cardiovascular diseases have a significantly increased risk of death when they are infected with SARS-CoV-2 (p < 0.001). A total of 16% (11/68) of the patients in the death group had secondary infections, and 1% (1/82) of the patients in the discharge group had secondary infections (p = 0.0018). Laboratory results showed that there were significant differences in white blood cell counts, absolute values of lymphocytes, platelets, albumin, total bilirubin, blood urea nitrogen, blood creatinine, myoglobin, cardiac troponin, C-reactive protein (CRP) and interleukin-6 (IL-6) between the two groups (Fig. 1b and Supplementary Table 1). The survival times of the enrolled patients in the death group were analyzed. The distribution of survival time from disease onset to death showed two peaks, with the first one at approximately 14 days (22 cases) and the second one at approximately 22 days (17 cases) (Fig. 1c). An analysis of the cause of death was performed. Among the 68 fatal cases, 36 patients (53%) died of respiratory failure, five patients (7%) with myocardial damage died of circulatory failure, 22 patients (33%) died of both, and five remaining died of an unknown cause (Fig. 1d). Based on the analysis of the clinical data, we confirmed that some patients died of fulminant myocarditis. In this study, we first reported that the infection of SARS-CoV-2 may cause fulminant myocarditis. Given that fulminant myocarditis is characterized by a rapid progress and a severe state of illness [3], our results should alert physicians to pay attention not only to the symptoms of respiratory dysfunction but also the symptoms of cardiac injury. *Correspondence: songsingsjx@sina.com 4 Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China Full author information is available at the end of the article

3,868 citations

Journal ArticleDOI
28 May 2020-Cell
TL;DR: It is proposed that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

3,286 citations


Additional excerpts

  • ...However, current research shows that induction of interferons in cells infected with SARS-CoV-2 is impaired [18, 20, 21]....

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Journal ArticleDOI
10 Oct 2001-JAMA
TL;DR: In this article, the authors evaluated the usefulness of repeated measurement of the Sequential Organ Failure Assessment (SOFA) score for prediction of mortality in intensive care unit (ICU) patients.
Abstract: ContextEvaluation of trends in organ dysfunction in critically ill patients may help predict outcome.ObjectiveTo determine the usefulness of repeated measurement the Sequential Organ Failure Assessment (SOFA) score for prediction of mortality in intensive care unit (ICU) patients.DesignProspective, observational cohort study conducted from April 1 to July 31, 1999.SettingA 31-bed medicosurgical ICU at a university hospital in Belgium.PatientsThree hundred fifty-two consecutive patients (mean age, 59 years) admitted to the ICU for more than 24 hours for whom the SOFA score was calculated on admission and every 48 hours until discharge.Main Outcome MeasuresInitial SOFA score (0-24), Δ-SOFA scores (differences between subsequent scores), and the highest and mean SOFA scores obtained during the ICU stay and their correlations with mortality.ResultsThe initial, highest, and mean SOFA scores correlated well with mortality. Initial and highest scores of more than 11 or mean scores of more than 5 corresponded to mortality of more than 80%. The predictive value of the mean score was independent of the length of ICU stay. In univariate analysis, mean and highest SOFA scores had the strongest correlation with mortality, followed by Δ-SOFA and initial SOFA scores. The area under the receiver operating characteristic curve was largest for highest scores (0.90; SE, 0.02; P<.001 vs initial score). When analyzing trends in the SOFA score during the first 96 hours, regardless of the initial score, the mortality rate was at least 50% when the score increased, 27% to 35% when it remained unchanged, and less than 27% when it decreased. Differences in mortality were better predicted in the first 48 hours than in the subsequent 48 hours. There was no significant difference in the length of stay among these groups. Except for initial scores of more than 11 (mortality rate >90%), a decreasing score during the first 48 hours was associated with a mortality rate of less than 6%, while an unchanged or increasing score was associated with a mortality rate of 37% when the initial score was 2 to 7 and 60% when the initial score was 8 to 11.ConclusionsSequential assessment of organ dysfunction during the first few days of ICU admission is a good indicator of prognosis. Both the mean and highest SOFA scores are particularly useful predictors of outcome. Independent of the initial score, an increase in SOFA score during the first 48 hours in the ICU predicts a mortality rate of at least 50%.

2,190 citations


"Serum Protein Profiling Reveals a S..." refers methods in this paper

  • ...The severity of illness was assessed using the Sequential Organ Failure Assessment (SOFA) score [9]....

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Journal ArticleDOI
13 Jul 2020-Science
TL;DR: The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections.
Abstract: Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression suggesting diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A unique phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor NF-κB and characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling. These data suggest that type-I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.

2,171 citations


"Serum Protein Profiling Reveals a S..." refers background or methods in this paper

  • ...In line with this, we observed a positive correlation of GRN with IL-6 abundance and disease severity in patients with COVID-19....

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  • ...Patients with high GRN expression showed higher maximum serum creatinine and IL-6 levels as surrogate parameters for disease severity (Fig....

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  • ...Transcriptional profiling of human airway epithelial cells revealed an upregulation of IL-6 and other pro-inflammatory cytokines but a repression of interferon I and III signaling after SARS-CoV-2 infection [18]....

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  • ...However, increased levels of IL-6 have been described in numerous conditions including trauma, surgery, sepsis, respiratory failure, myocardial infarction, or post-resuscitation syndrome [8] and can be considered as a general indicator of disease severity....

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  • ...The lack of Ac ce pte d M an us cri pt interferons is associated with a persistent blood viral load and an increase of TNF-α and IL-6 [26], suggesting that the diminished interferon response contributes to impaired virus elimination and disease progression in COVID-19....

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