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1.
Cell Rep ; 38(2): 110205, 2022 01 11.
Article in English | MEDLINE | ID: covidwho-1588142

ABSTRACT

Spontaneous mutations introduce uncertainty into coronavirus disease 2019 (COVID-19) control procedures and vaccine development. Here, we perform a spatiotemporal analysis on intra-host single-nucleotide variants (iSNVs) in 402 clinical samples from 170 affected individuals, which reveals an increase in genetic diversity over time after symptom onset in individuals. Nonsynonymous mutations are overrepresented in the pool of iSNVs but underrepresented at the single-nucleotide polymorphism (SNP) level, suggesting a two-step fitness selection process: a large number of nonsynonymous substitutions are generated in the host (positive selection), and these substitutions tend to be unfixed as SNPs in the population (negative selection). Dynamic iSNV changes in subpopulations with different gender, age, illness severity, and viral shedding time displayed a varied fitness selection process among populations. Our study highlights that iSNVs provide a mutational pool shaping the rapid global evolution of the virus.

2.
Front Immunol ; 12: 735125, 2021.
Article in English | MEDLINE | ID: covidwho-1441109

ABSTRACT

Background: The global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection. Methods: A total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3-7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally. Results: We revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients. Conclusions: Our findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immune System Diseases/immunology , SARS-CoV-2 , Adult , Aged , CD8 Antigens/immunology , Cytokines/immunology , Female , HLA-DR Antigens/immunology , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Young Adult
3.
BMC Infect Dis ; 21(1): 885, 2021 Aug 30.
Article in English | MEDLINE | ID: covidwho-1379783

ABSTRACT

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) posed an enormous threat to public health. The use of antiviral drugs in patients with this disease have triggered people's attentions. Whether interferon alfa-2b or lopinavir/ritonavir (LPV/r) plus interferon alfa-2b treatment can against SARS-CoV-2 was unknown. The objectives of this study was to evaluate the efficacy and safety of interferon alfa-2b and LPV/r plus interferon alfa-2b for SARS-CoV-2 infection in adult patients hospitalized with COVID-19. METHODS: This is a retrospective cohort study of 123 patients confirmed SARS-CoV-2 infection by PCR on nasopharyngeal swab and symptoms between Jan. 13 and Apr. 23, 2020. All patients received standard supportive care and regular clinical monitoring. Patients were assigned to standard care group (n = 12), interferon alfa-2b group (n = 44), and combination LPV/r plus interferon alfa-2b group (n = 67). The primary endpoints were duration of required oxygen support and virus clearance time. Associations between therapies and these outcomes were assessed by Cox proportional hazards regression. RESULTS: Baseline clinical characteristics were not significantly different among the three groups (P > 0.05). No significant associations were observed between LPV/r/interferon alfa-2b and faster SARS-CoV-2 RNA clearance (HR, 0.85 [95% confidence interval (CI) 0.45-1.61]; P = 0.61 in interferon alfa-2b group vs HR, 0.59 [95% CI 0.32-1.11]; P = 0.10 in LPV/r plus interferon alfa-2b group). Individual therapy groups also showed no significant association with duration of required oxygen support. There were no significant differences among the three groups in the incidence of adverse events (P > 0.05). CONCLUSIONS: In patients with confirmed SARS-CoV-2 infection, no benefit was observed from interferon alfa-2b or LPV/r plus interferon alfa-2b treatment. The findings may provide references for treatment guidelines of patients with SARS-CoV-2 infection.


Subject(s)
COVID-19 , Ritonavir , Adult , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Combinations , Humans , Interferon alpha-2 , Lopinavir/therapeutic use , RNA, Viral , Retrospective Studies , Ritonavir/therapeutic use , SARS-CoV-2
5.
Natl Sci Rev ; 8(4): nwab006, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1254806

ABSTRACT

After a short recovery period, COVID-19 reinfections could occur in convalescent patients, even those with measurable levels of neutralizing antibodies. Effective vaccinations and protective public health measures are recommended for the convalescent COVID-19 patients.

6.
Front Med (Lausanne) ; 8: 629828, 2021.
Article in English | MEDLINE | ID: covidwho-1127988

ABSTRACT

We reported that the complete genome sequence of SARS-Coronavirus-2 (SARS-CoV-2) was obtained from a cerebrospinal fluid (CSF) sample by ultrahigh-depth sequencing. Fourteen days after onset, seizures, maxillofacial convulsions, intractable hiccups and a significant increase in intracranial pressure developed in an adult coronavirus disease 2019 patient. The complete genome sequence of SARS-CoV-2 obtained from the cerebrospinal fluid indicates that SARS-CoV-2 can invade the central nervous system. In future, along with nervous system assessment, the pathogen genome detection and other indicators are needed for studying possible nervous system infection of SARS-CoV-2.

7.
Microbes Infect ; 23(4-5): 104806, 2021.
Article in English | MEDLINE | ID: covidwho-1120151

ABSTRACT

This study aimed to investigate the frequency and characteristics of respiratory co-infections in COVID-19 patients in the intensive care unit (ICU). In this retrospective observational study, pathogens responsible for potential co-infections were detected by the bacterial culture, real-time polymerase chain reaction (RT-PCR), or serological fungal antigen tests. Demographic and clinical characteristics, as well as microbial results, were analyzed. Bacterial culture identified 56 (58.3%) positive samples for respiratory pathogens, with the most common bacteria being Burkholderia cepacia (18, 18.8%). RT-PCR detected 38 (76.0%) and 58 (87.9%) positive results in the severe and critical groups, respectively. Most common pathogens detected were Stenotrophomonas maltophilia (28.0%) and Pseudomonas aeruginosa (28.0%) in the severe group and S. maltophilia (45.5%) in the critical group. P. aeruginosa was detected more during the early stage after ICU admission. Acinetobacter baumannii and Staphylococcus aureus were more frequently identified during late ICU admission. Fungal serum antigens were more frequently positive in the critical group than in the severe group, and the positive rate of fungal serum antigens frequency increased with prolonged ICU stay. A high frequency of respiratory co-infections presented in ICU COVID-19 patients. Careful examinations and necessary tests should be performed to exclude these co-infections.


Subject(s)
Bacterial Infections/epidemiology , COVID-19/epidemiology , Coinfection/epidemiology , Mycoses/epidemiology , Adult , Aged , Aged, 80 and over , Bacterial Infections/virology , COVID-19/microbiology , China/epidemiology , Coinfection/microbiology , Coinfection/virology , Female , Humans , Intensive Care Units , Male , Middle Aged , Mycoses/virology , Respiratory Tract Infections/epidemiology
8.
Front Pharmacol ; 11: 634266, 2020.
Article in English | MEDLINE | ID: covidwho-1110322

ABSTRACT

Background: Yindan Jiedu Granules (YDJDG) have been newly prescribed as a Chinese herbal formula. This study aimed to compare the efficacy of YDJDG and lopinavir-ritonavir in the treatment of coronavirus disease 2019 (COVID-19). Methods: Overall, 131 patients with COVID-19 were included in this study. In addition to standard care, 60 of these patients received YDJDG (YDJDG group) and 71 received lopinavir-ritonavir (lopinavir-ritonavir group). Propensity score matching (PSM) was used to match the characteristics of individuals in the two groups, while the Kaplan-Meier method was used to compare the proportion recovery observed. Results: Cox analysis revealed that YDJDG and CD4 ≥ 660 cells/µL were independent predictive factors of proportion recovery. At baseline, disease types differed between the YDJDG and lopinavir-ritonavir treatment groups. Furthermore, no significant adverse effects or toxicities relevant to YDJDG were observed. The median recovery time was 21 days in the YDJDG group and 27 days in the lopinavir-ritonavir group. After PSM (1:1), 50 patient pairs, YDJDG vs. lopinavir-ritonavir, were analyzed. In the YDJDG group, the proportion of recovered patients was remarkably higher than that observed in the lopinavir-ritonavir group (p = 0.0013), especially for those presenting mild/moderate disease type and CD4 < 660 cells/µL. In the YDJDG group, the mean duration of fever and pulmonary exudative lesions was significantly shorter than that observed in the lopinavir-ritonavir group (p = 0.0180 and p = 0.0028, respectively). Conclusion: YDJDG reveals the potential to hasten the recovery period in COVID-19 patients with mild/moderate disease type or CD4 < 660 cells/µL by shortening the mean duration of fever and pulmonary exudative lesions.

9.
Front Immunol ; 12: 603563, 2021.
Article in English | MEDLINE | ID: covidwho-1090415

ABSTRACT

The high infection rate and rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) make it a world-wide pandemic. Individuals infected by the virus exhibited different degrees of symptoms, and most convalescent individuals have been shown to develop both cellular and humoral immune responses. However, virus-specific adaptive immune responses in severe patients during acute phase have not been thoroughly studied. Here, we found that in a group of COVID-19 patients with acute respiratory distress syndrome (ARDS) during hospitalization, most of them mounted SARS-CoV-2-specific antibody responses, including neutralizing antibodies. However, compared to healthy controls, the percentages and absolute numbers of both NK cells and CD8+ T cells were significantly reduced, with decreased IFNγ expression in CD4+ T cells in peripheral blood from severe patients. Most notably, their peripheral blood lymphocytes failed in producing IFNγ against viral proteins. Thus, severe COVID-19 patients at acute infection stage developed SARS-CoV-2-specific antibody responses but were impaired in cellular immunity, which emphasizes on the role of cellular immunity in COVID-19.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Killer Cells, Natural/immunology , Respiratory Distress Syndrome/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Cell Count , Cells, Cultured , Disease Progression , Female , Humans , Immunity, Cellular , Interferon-gamma/metabolism , Male , Middle Aged
10.
Crit Care ; 25(1): 51, 2021 02 08.
Article in English | MEDLINE | ID: covidwho-1069580

ABSTRACT

BACKGROUND: Thrombosis and coagulopathy are highly prevalent in critically ill patients with COVID-19 and increase the risk of death. Immunothrombosis has recently been demonstrated to contribute to the thrombotic events in COVID-19 patients with coagulopathy. As the primary components of immunothrombosis, neutrophil extracellular traps (NETs) could be induced by complement cascade components and other proinflammatory mediators. We aimed to explore the clinical roles of NETs and the regulation of complement on the NET formation in COVID-19. METHODS: We recruited 135 COVID-19 patients and measured plasma levels of C5, C3, cell-free DNA and myeloperoxidase (MPO)-DNA. Besides, the formation of NETs was detected by immunofluorescent staining and the cytotoxicity to vascular endothelial HUVEC cells was evaluated by CCK-8 assay. RESULTS: We found that the plasma levels of complements C3 and MPO-DNA were positively related to coagulation indicator fibrin(-ogen) degradation products (C3: r = 0.300, p = 0.005; MPO-DNA: r = 0.316, p = 0.002) in COVID-19 patients. Besides, C3 was positively related to direct bilirubin (r = 0.303, p = 0.004) and total bilirubin (r = 0.304, p = 0.005), MPO-DNA was positively related to lactate dehydrogenase (r = 0.306, p = 0.003) and creatine kinase (r = 0.308, p = 0.004). By using anti-C3a and anti-C5a antibodies, we revealed that the complement component anaphylatoxins in the plasma of COVID-19 patients strongly induced NET formation. The pathological effect of the anaphylatoxin-NET axis on the damage of vascular endothelial cells could be relieved by recombinant carboxypeptidase B (CPB), a stable homolog of enzyme CPB2 which can degrade anaphylatoxins to inactive products. CONCLUSIONS: Over-activation in anaphylatoxin-NET axis plays a pathological role in COVID-19. Early intervention in anaphylatoxins might help prevent thrombosis and disease progression in COVID-19 patients.


Subject(s)
Anaphylatoxins/metabolism , COVID-19/drug therapy , COVID-19/immunology , Carboxypeptidase B/metabolism , Carboxypeptidase B/therapeutic use , Extracellular Traps/drug effects , Neutrophils/drug effects , Thrombosis/prevention & control , Adult , Aged , COVID-19/physiopathology , Extracellular Traps/immunology , Female , Humans , Male , Middle Aged , Neutrophils/immunology , Thrombosis/immunology
11.
Nat Commun ; 11(1): 5503, 2020 10 30.
Article in English | MEDLINE | ID: covidwho-894393

ABSTRACT

The spread of SARS-CoV-2 in Beijing before May, 2020 resulted from transmission following both domestic and global importation of cases. Here we present genomic surveillance data on 102 imported cases, which account for 17.2% of the total cases in Beijing. Our data suggest that all of the cases in Beijing can be broadly classified into one of three groups: Wuhan exposure, local transmission and overseas imports. We classify all sequenced genomes into seven clusters based on representative high-frequency single nucleotide polymorphisms (SNPs). Genomic comparisons reveal higher genomic diversity in the imported group compared to both the Wuhan exposure and local transmission groups, indicating continuous genomic evolution during global transmission. The imported group show region-specific SNPs, while the intra-host single nucleotide variations present as random features, and show no significant differences among groups. Epidemiological data suggest that detection of cases at immigration with mandatory quarantine may be an effective way to prevent recurring outbreaks triggered by imported cases. Notably, we also identify a set of novel indels. Our data imply that SARS-CoV-2 genomes may have high mutational tolerance.


Subject(s)
Betacoronavirus/growth & development , Coronavirus Infections/virology , Pneumonia, Viral/virology , Adult , Beijing/epidemiology , COVID-19 , Coronavirus Infections/epidemiology , Female , Genome, Viral , Genomics , Genotype , Humans , Male , Middle Aged , Mutation , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Polymorphism, Single Nucleotide , SARS-CoV-2 , Travel , Young Adult
12.
Medicine (Baltimore) ; 99(34): e21874, 2020 Aug 21.
Article in English | MEDLINE | ID: covidwho-733315

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) has caused serious damage to public health. COVID-19 has no vaccine or specific therapy; its mortality rate increases significantly once patients deteriorate. Furthermore, intensive monitoring of COVID-19 is limited by insufficient medical resources and increased risks of exposure to medical staff. We therefore aim to build an early warning and rapid response system (EWRRS) to address these problems. METHOD: The research is designed as a prospective cohort study, to verify a dynamic and interactive evaluation system; it includes patient self-reporting, active monitoring, early alarming and treatment recommendations. Adult patients diagnosed with COVID-19 will be recruited from Sept 2020 to Aug 2021 at a tertiary contagious hospital. Patients with life expectancy <48 hours, pregnant or lactating, in immunosuppression states or end-stage diseases will be excluded. The intervention is implementation of EWRRS to detect early signs of clinical deterioration of COVID-19 patients, to provide timely and efficient treatment suggestions by the system. EWRRS can determine the classification and interactive evaluation of patient information; the determination is based on the application of 3 different scenario modules, separately driven by patients, nurses, and physicians. The primary outcome is change in disease severity category after treatment. Secondary outcomes include the proportion of patients with different disease severity types; critical deterioration events; patients who had unplanned transfers to an intensive care unit (ICU) and required critical care interventions; intervals from warning to implementation of clinical interventions; hospital mortality; length of ICU and hospital stay; workload of medical staff and risks of exposure to COVID-19. DISCUSSION: Our hypothesis is that EWRRS provides an example of an early identification, warning, and response system for COVID-19. In addition, EWRRS can potentially be extended to use as a grading metric for general critically ill patients in an ICU setting.


Subject(s)
Clinical Deterioration , Coronavirus Infections/physiopathology , Critical Illness , Pneumonia, Viral/physiopathology , Betacoronavirus , COVID-19 , Humans , Intensive Care Units , Monitoring, Physiologic , Pandemics , Prospective Studies , Research Design , Risk Assessment , SARS-CoV-2 , Severity of Illness Index
13.
Open Forum Infect Dis ; 7(5): ofaa169, 2020 May.
Article in English | MEDLINE | ID: covidwho-623975

ABSTRACT

Background: There is currently a lack of nonspecific laboratory indicators as a quantitative standard to distinguish between the 2019 coronavirus disease (COVID-19) and an influenza A or B virus infection. Thus, the aim of this study was to establish a nomogram to detect COVID-19. Methods: A nomogram was established using data collected from 457 patients (181 with COVID-19 and 276 with influenza A or B infection) in China. The nomogram used age, lymphocyte percentage, and monocyte count to differentiate COVID-19 from influenza. Results: Our nomogram predicted probabilities of COVID-19 with an area under the receiver operating characteristic curve of 0.913 (95% confidence interval [CI], 0.883-0.937), greater than that of the lymphocyte:monocyte ratio (0.849; 95% CI, 0.812-0.880; P = .0007), lymphocyte percentage (0.808; 95% CI, 0.768-0.843; P < .0001), monocyte count (0.780; 95% CI, 0.739-0.817; P < .0001), or age (0.656; 95% CI, 0.610-0.699; P < .0001). The predicted probability conformed to the real observation outcomes of COVID-19, according to the calibration curves. Conclusions: We found that age, lymphocyte percentage, and monocyte count are risk factors for the early-stage prediction of patients infected with the 2019 novel coronavirus. As such, our research provides a useful test for doctors to differentiate COVID-19 from influenza.

15.
Open Access (OA) Online-First Publ Res Pap COVID-19 ; : 328-335, 2020.
Article | WHO COVID | ID: covidwho-602832

ABSTRACT

A review. As a newly emerged and highly infectious respiratory disease, the COVID-19 is spreading around the world. This disease has infected millions of people and many of them die in the end. It is a serious threat to the safety of human life and property. We provide references for diagnosis and treatment of the COVID-19 by summarizing the characteristics and evolutions of the disease in clin. treatment.

16.
J Transl Med ; 18(1): 206, 2020 05 20.
Article in English | MEDLINE | ID: covidwho-324357

ABSTRACT

BACKGROUND: Patients with critical illness due to infection with the 2019 coronavirus disease (COVID-19) show rapid disease progression to acute respiratory failure. The study aimed to screen the most useful predictive factor for critical illness caused by COVID-19. METHODS: The study prospectively involved 61 patients with COVID-19 infection as a derivation cohort, and 54 patients as a validation cohort. The predictive factor for critical illness was selected using LASSO regression analysis. A nomogram based on non-specific laboratory indicators was built to predict the probability of critical illness. RESULTS: The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent risk factor for critical illness in patients with COVID-19 infection. The NLR had an area under receiver operating characteristic of 0.849 (95% confidence interval [CI], 0.707 to 0.991) in the derivation cohort and 0.867 (95% CI 0.747 to 0.944) in the validation cohort, the calibration curves fitted well, and the decision and clinical impact curves showed that the NLR had high standardized net benefit. In addition, the incidence of critical illness was 9.1% (1/11) for patients aged ≥ 50 and having an NLR < 3.13, and 50% (7/14) patients with age ≥ 50 and NLR ≥ 3.13 were predicted to develop critical illness. Based on the risk stratification of NLR according to age, this study has developed a COVID-19 pneumonia management process. CONCLUSIONS: We found that NLR is a predictive factor for early-stage prediction of patients infected with COVID-19 who are likely to develop critical illness. Patients aged ≥ 50 and having an NLR ≥ 3.13 are predicted to develop critical illness, and they should thus have rapid access to an intensive care unit if necessary.


Subject(s)
Coronavirus Infections/diagnosis , Critical Illness , Lymphocytes/pathology , Neutrophils/pathology , Pneumonia, Viral/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Betacoronavirus/pathogenicity , COVID-19 , Child , Child, Preschool , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/pathology , Disease Progression , Female , History, 21st Century , Humans , Infant , Leukocyte Count , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Prognosis , Prospective Studies , SARS-CoV-2 , Severity of Illness Index , Young Adult
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