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1.
EBioMedicine ; 75: 103789, 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1587925

ABSTRACT

BACKGROUND: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial. METHODS: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102). FINDINGS: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups. INTERPRETATION: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients. FUNDING: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

2.
Preprint in English | EuropePMC | ID: ppcovidwho-294959

ABSTRACT

In multi-agent reinforcement learning (MARL), it is challenging for a collection of agents to learn complex temporally extended tasks. The difficulties lie in computational complexity and how to learn the high-level ideas behind reward functions. We study the graph-based Markov Decision Process (MDP) where the dynamics of neighboring agents are coupled. We use a reward machine (RM) to encode each agent's task and expose reward function internal structures. RM has the capacity to describe high-level knowledge and encode non-Markovian reward functions. We propose a decentralized learning algorithm to tackle computational complexity, called decentralized graph-based reinforcement learning using reward machines (DGRM), that equips each agent with a localized policy, allowing agents to make decisions independently, based on the information available to the agents. DGRM uses the actor-critic structure, and we introduce the tabular Q-function for discrete state problems. We show that the dependency of Q-function on other agents decreases exponentially as the distance between them increases. Furthermore, the complexity of DGRM is related to the local information size of the largest $κ$-hop neighborhood, and DGRM can find an $O(ρ

3.
Jianzhu Jieneng = Construction Conserves Energy ; 49(6):87, 2021.
Article in English | ProQuest Central | ID: covidwho-1342760

ABSTRACT

In the first half of 2020, the construction of Shanghai Library(East Zone) was delayed by the COVID-19's outbreak. As time goes on, the epidemic is spreading in many parts of the world. Although the epidemic in China has been effectively controlled, such grave public health emergencies ring the alarm bell for social public. Relative authorities have issued guidelines, measures and specifications for how to use HVAC system under these circumstances. By analyzing these new codes and standards, the HVAC system in Shanghai Library(East Zone) can operate as design. Because the design outdoor air rates and filter's performance meet the standard requirements. At the end of Shanghai Library East's construction, some operation methods and adaptable improvements in filters are given to increase the security level. Five methods, including:(1)enhancement of natural ventilation,(2)control of the occupant density,(3)installation of filters,(4)increase of the outdoor air rates for ventilation according to the risk level of epidemic situation,(5)cleaning, disinfection and inspection of the HVAC equipment. Given by this research can also be applied to similar public buildings.

4.
Nat Metab ; 3(7): 909-922, 2021 07.
Article in English | MEDLINE | ID: covidwho-1279905

ABSTRACT

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane1. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes2,3, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Extracellular Vesicles/metabolism , Lipidomics , Metabolomics , SARS-CoV-2 , Biological Transport , COVID-19/epidemiology , Cell Fractionation , Cell Membrane/metabolism , Chemical Fractionation , Cluster Analysis , Computational Biology/methods , Exosomes/metabolism , Host-Pathogen Interactions , Humans , Lipidomics/methods , Metabolome , Metabolomics/methods , Retrospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/immunology
5.
Eur J Med Res ; 26(1): 45, 2021 May 14.
Article in English | MEDLINE | ID: covidwho-1229005

ABSTRACT

BACKGROUND: Hematological comparison of coronavirus disease (COVID-19) and other viral pneumonias can provide insights into COVID-19 treatment. METHODS: In this retrospective case-control single-center study, we compared the data of 126 patients with viral pneumonia during different outbreaks [severe acute respiratory syndrome (SARS) in 2003, influenza A (H1N1) in 2009, human adenovirus type 7 in 2018, and COVID-19 in 2020]. RESULTS: One of the COVID-19 characteristics was a continuous decline in the hemoglobin level. The neutrophil count was related to the aggravation of COVID-19 and SARS. Thrombocytopenia occurred in patients with SARS and severe COVID-19 even at the recovery stage. Lymphocytes were related to the entire course of adenovirus infection, recovery of COVID-19, and disease development of SARS. CONCLUSIONS: Dynamic changes in hematological counts could provide a reference for the pathogenesis and prognosis of pneumonia caused by respiratory viruses in clinics.


Subject(s)
Adenovirus Infections, Human/blood , COVID-19/blood , Influenza, Human/blood , Pneumonia, Viral/blood , Severe Acute Respiratory Syndrome/blood , Adenovirus Infections, Human/pathology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/pathology , Case-Control Studies , Female , Hemoglobins/analysis , Humans , Influenza, Human/pathology , Lymphocyte Count , Male , Middle Aged , Neutrophils/cytology , Pneumonia, Viral/pathology , Retrospective Studies , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/pathology , Thrombocytopenia/pathology , Young Adult
6.
PLoS One ; 16(3): e0247660, 2021.
Article in English | MEDLINE | ID: covidwho-1119473

ABSTRACT

Ever since the outbreak of the COVID-19 epidemic, various public health control strategies have been proposed and tested against the coronavirus SARS-CoV-2. We study three specific COVID-19 epidemic control models: the susceptible, exposed, infectious, recovered (SEIR) model with vaccination control; the SEIR model with shield immunity control; and the susceptible, un-quarantined infected, quarantined infected, confirmed infected (SUQC) model with quarantine control. We express the control requirement in metric temporal logic (MTL) formulas (a type of formal specification languages) which can specify the expected control outcomes such as "the deaths from the infection should never exceed one thousand per day within the next three months" or "the population immune from the disease should eventually exceed 200 thousand within the next 100 to 120 days". We then develop methods for synthesizing control strategies with MTL specifications. To the best of our knowledge, this is the first paper to systematically synthesize control strategies based on the COVID-19 epidemic models with formal specifications. We provide simulation results in three different case studies: vaccination control for the COVID-19 epidemic with model parameters estimated from data in Lombardy, Italy; shield immunity control for the COVID-19 epidemic with model parameters estimated from data in Lombardy, Italy; and quarantine control for the COVID-19 epidemic with model parameters estimated from data in Wuhan, China. The results show that the proposed synthesis approach can generate control inputs such that the time-varying numbers of individuals in each category (e.g., infectious, immune) satisfy the MTL specifications. The results also show that early intervention is essential in mitigating the spread of COVID-19, and more control effort is needed for more stringent MTL specifications. For example, based on the model in Lombardy, Italy, achieving less than 100 deaths per day and 10000 total deaths within 100 days requires 441.7% more vaccination control effort than achieving less than 1000 deaths per day and 50000 total deaths within 100 days.


Subject(s)
COVID-19/prevention & control , Quarantine , Vaccination , Algorithms , COVID-19/epidemiology , COVID-19/immunology , China/epidemiology , Computer Simulation , Humans , Immunity , Italy/epidemiology , Models, Biological , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
8.
Signal Transduct Target Ther ; 6(1): 58, 2021 02 10.
Article in English | MEDLINE | ID: covidwho-1078577

ABSTRACT

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.


Subject(s)
COVID-19/therapy , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , SARS-CoV-2 , Umbilical Cord , Aged , Allografts , COVID-19/mortality , COVID-19/physiopathology , Double-Blind Method , Female , Humans , Male , Middle Aged , Treatment Outcome
9.
Health Policy Technol ; 2020 Sep 15.
Article in English | MEDLINE | ID: covidwho-761733
10.
Infect Dis Poverty ; 9(1): 161, 2020 Nov 25.
Article in English | MEDLINE | ID: covidwho-949105

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is pandemic. It is critical to identify COVID-19 patients who are most likely to develop a severe disease. This study was designed to determine the clinical and epidemiological features of COVID-19 patients associated with the development of pneumonia and factors associated with disease progression. METHODS: Seventy consecutive patients with etiologically confirmed COVID-19 admitted to PLA General Hospital in Beijing, China from December 27, 2019 to March 12, 2020 were enrolled in this study and followed-up to March 16, 2020. Differences in clinical and laboratory findings between COVID-19 patients with pneumonia and those without were determined by the χ2 test or the Fisher exact test (categorical variables) and independent group t test or Mann-Whitney U test (continuous variables). The Cox proportional hazard model and Generalized Estimating Equations were applied to evaluate factors that predicted the progression of COVID-19. RESULTS: The mean incubation was 8.67 (95% confidence interval, 6.78-10.56) days. Mean duration from the first test severe acute respiratory syndrome coronavirus 2-positive to conversion was 11.38 (9.86-12.90) days. Compared to pneumonia-free patients, pneumonia patients were 16.5 years older and had higher frequencies of having hypertension, fever, and cough and higher circulating levels of neutrophil proportion, interleukin-6, low count (< 190/µl) of CD8+ T cells, and neutrophil/lymphocyte ratio. Thirteen patients deteriorated during hospitalization. Cox regression analysis indicated that older age and higher serum levels of interleukin-6, C-reactive protein, procalcitonin, and lactate at admission significantly predicted the progression of COVID-19. During hospitalization, circulating counts of T lymphocytes, CD4+ T cells, and CD8+ T cells were lower, whereas neutrophil proportion, neutrophil/lymphocyte ratio, and the circulating levels of interleukin-6, C-reactive protein, and procalcitonin were higher, in pneumonia patients than in pneumonia-free patients. CD8+ lymphocyte count in pneumonia patients did not recover when discharged. CONCLUSIONS: Older age and higher levels of C-reactive protein, procalcitionin, interleukin-6, and lactate might predict COVID-19 progression. T lymphocyte, especially CD8+ cell-mediated immunity is critical in recovery of COVID-19. This study may help in predicting disease progression and designing immunotherapy for COVID-19.


Subject(s)
CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Interleukin-6/blood , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , Child , Child, Preschool , China/epidemiology , Disease Progression , Female , Hospitalization , Humans , Leukocyte Count , Male , Middle Aged , Neutrophils/pathology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Risk Factors , SARS-CoV-2 , Young Adult
12.
Preprint | SSRN | ID: ppcovidwho-513

ABSTRACT

Background: With the outbreak of COVID-19 from Wuhan, HubeProvince, China since January 2020, there is a tremendous pressure on medical resources. We studie

13.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733534

ABSTRACT

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Cord Blood Stem Cell Transplantation/methods , Coronavirus Infections/therapy , Hematopoietic Stem Cells/virology , Mesenchymal Stem Cell Transplantation/methods , Pneumonia, Viral/therapy , Adult , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Combinations , Female , Glucocorticoids/therapeutic use , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiration, Artificial , Ritonavir , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
14.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Article in English | MEDLINE | ID: covidwho-710376

ABSTRACT

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Betacoronavirus/immunology , Coronavirus Infections/immunology , Interferon Type I/metabolism , Pneumonia, Viral/immunology , Receptors, Immunologic/metabolism , Adolescent , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19 , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , GPI-Linked Proteins/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , RNA-Seq , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , SARS-CoV-2 , Severity of Illness Index , Single-Cell Analysis
15.
Jpn J Infect Dis ; 74(1): 54-60, 2021 Jan 22.
Article in English | MEDLINE | ID: covidwho-693628

ABSTRACT

This study aimed to analyze the clinical characteristics and potential predictors of disease severity in patients with coronavirus disease 2019 (COVID-19). We retrospectively analyzed the clinical data from 64 (37 male and 27 female) patients with COVID-19. Their mean age was 47.8 years; 43 (67.2%) cases were non-severe, 21 (32.8%) were severe, and 2 patients (3.1%) died. Age and serum ferritin levels were significantly associated with COVID-19 severity. There were no significant differences in the duration of severe illness or the number of days on high-level respiratory support between the low-dose and high-dose methylprednisolone groups. The mean number of days in hospital in the high-dose group was higher than that in the low-dose group. Repeated monitoring of ferritin, interleukin-6, C-reactive protein, lactic acid dehydrogenase, and erythrocyte sedimentation rate during COVID-19 treatment may assist in the prediction of disease severity and evaluation of treatment effects.


Subject(s)
COVID-19/diagnosis , COVID-19/pathology , SARS-CoV-2 , Severity of Illness Index , Adult , Aged , COVID-19/drug therapy , COVID-19/epidemiology , China/epidemiology , Female , Glucocorticoids/therapeutic use , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors
16.
Chin J Integr Med ; 26(9): 648-655, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-648556

ABSTRACT

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS: Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).


Subject(s)
Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/administration & dosage , Interferon-alpha/administration & dosage , Lopinavir/administration & dosage , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Administration, Inhalation , Adult , COVID-19 , China , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Integrative Medicine , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Risk Assessment , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/mortality , Severity of Illness Index , Survival Rate
17.
Nat Commun ; 11(1): 3410, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-635899

ABSTRACT

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , Biomarkers/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19 , Chemotaxis, Leukocyte , China/epidemiology , Coronavirus Infections/blood , Coronavirus Infections/virology , Cytokines/blood , Female , Humans , Inflammation , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Leukocyte Count , Lung/immunology , Lung/virology , Lymphocyte Activation , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology , SARS-CoV-2
18.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-612608

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/pathology , Exosomes/metabolism , G(M3) Ganglioside/blood , Gangliosides/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Adult , Aged , Betacoronavirus , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19 , Diglycerides/blood , Female , Humans , Male , Metabolome/physiology , Metabolomics/methods , Middle Aged , Pandemics , SARS-CoV-2 , Sphingomyelins/blood , Tandem Mass Spectrometry , Young Adult
19.
J Allergy Clin Immunol Pract ; 8(8): 2585-2591.e1, 2020 09.
Article in English | MEDLINE | ID: covidwho-609222

ABSTRACT

BACKGROUND: The clinical management of coronavirus disease 2019 (COVID-19) is dependent on understanding the underlying factors that contribute to the disease severity. In the absence of effective antiviral therapies, other host immunomodulatory therapies such as targeting inflammatory response are currently being used without clear evidence of their effectiveness. Because inflammation is an essential component of host antiviral mechanisms, therapies targeting inflammation may adversely affect viral clearance and disease outcome. OBJECTIVE: To understand whether the persistent presence of the virus is a key determinant in the disease severity during COVID-19 and to determine whether the viral reactivation in some patients is associated with infectious viral particles. METHODS: The data for patients were available including the onset of the disease, duration of viral persistence, measurements of inflammatory markers such as IL-6 and C-reactive protein, chest imaging, disease symptoms, and their durations among others. Follow-up tests were performed to determine whether the viral negative status persists after their recovery. RESULTS: Our data show that patients with persistent viral presence (>16 days) have more severe disease outcomes including extensive lung involvement and requirement of respiratory support. Two patients who died of COVID-19 were virus-positive at the time of their death. Four patients demonstrated virus-positive status on the follow-up tests, and these patient samples were sent to viral culture facility where virus culture could not be established. CONCLUSIONS: These data suggest that viral persistence is the key determining factor of the disease severity. Therapies that may impair the viral clearance may impair the host recovery from COVID-19.


Subject(s)
Coronavirus Infections/physiopathology , Inflammation/physiopathology , Pneumonia, Viral/physiopathology , Adolescent , Adult , Aged , Betacoronavirus , C-Reactive Protein/immunology , COVID-19 , Child , Child, Preschool , Comorbidity , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Female , Glucocorticoids/therapeutic use , Humans , Infant , Inflammation/epidemiology , Inflammation/immunology , Inflammation Mediators/immunology , Interleukin-6/immunology , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Real-Time Polymerase Chain Reaction , Respiration, Artificial , SARS-CoV-2 , Severity of Illness Index , Young Adult
20.
Lancet HIV ; 7(8): e524-e526, 2020 08.
Article in English | MEDLINE | ID: covidwho-401816
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