Elevated glucose level leads to rapid COVID-19 progression and high fatality.

OBJECTIVES: We aimed to identify high-risk factors for disease progression and fatality for coronavirus disease 2019 (COVID-19) patients. METHODS: We enrolled 2433 COVID-19 patients and used LASSO regression and multivariable cause-specific Cox proportional hazard models to identify the risk factors for disease progression and fatality. RESULTS: The median time for progression from mild-to-moderate, moderate-to-severe, severe-to-critical, and critical-to-death were 3.0 (interquartile range: 1.8-5.5), 3.0 (1.0-7.0), 3.0 (1.0-8.0), and 6.5 (4.0-16.3) days, respectively. Among 1,758 mild or moderate patients at admission, 474 (27.0%) progressed to a severe or critical stage. Age above 60 years, elevated levels of blood glucose, respiratory rate, fever, chest tightness, c-reaction protein, lactate dehydrogenase, direct bilirubin, and low albumin and lymphocyte count were significant risk factors for progression. Of 675 severe or critical patients at admission, 41 (6.1%) died. Age above 74 years, elevated levels of blood glucose, fibrinogen and creatine kinase-MB, and low plateleta count were significant risk factors for fatality. Patients with elevated blood glucose level were 58% more likely to progress and 3.22 times more likely to die of COVID-19. CONCLUSIONS: Older age, elevated glucose level, and clinical indicators related to systemic inflammatory responses and multiple organ failures, predict both the disease progression and the fatality of COVID-19 patients.

Prediction for Progression Risk in Patients With COVID-19 Pneumonia: The CALL Score.

BACKGROUND: We aimed to clarify high-risk factors for coronavirus disease 2019 (COVID-19) with multivariate analysis and establish a predictive model of disease progression to help clinicians better choose a therapeutic strategy. METHODS: All consecutive patients with COVID-19 admitted to Fuyang Second People's Hospital or the Fifth Medical Center of Chinese PLA General Hospital between 20 January and 22 February 2020 were enrolled and their clinical data were retrospectively collected. Multivariate Cox regression was used to identify risk factors associated with progression, which were then were incorporated into a nomogram to establish a novel prediction scoring model. ROC was used to assess the performance of the model. RESULTS: Overall, 208 patients were divided into a stable group (n = 168, 80.8%) and a progressive group (n = 40,19.2%) based on whether their conditions worsened during hospitalization. Univariate and multivariate analyses showed that comorbidity, older age, lower lymphocyte count, and higher lactate dehydrogenase at presentation were independent high-risk factors for COVID-19 progression. Incorporating these 4 factors, the nomogram achieved good concordance indexes of .86 (95% confidence interval [CI], .81-.91) and well-fitted calibration curves. A novel scoring model, named as CALL, was established; its area under the ROC was .91 (95% CI, .86-.94). Using a cutoff of 6 points, the positive and negative predictive values were 50.7% (38.9-62.4%) and 98.5% (94.7-99.8%), respectively. CONCLUSIONS: Using the CALL score model, clinicians can improve the therapeutic effect and reduce the mortality of COVID-19 with more accurate and efficient use of medical resources.

[Rapid establishment of traditional Chinese medicine prevention and treatment of 2019-nCoV based on clinical experience and molecular docking].

The coronavirus disease 2019(COVID-19) is raging in China and more than 20 other countries and regions since the middle of December 2019. Currently, there is no specific drug or vaccine besides symptomatic supportive therapy. Taking full advantage of the clinical experience of traditional Chinese medicine(TCM) in preventing and controlling major epidemics such as SARS, it is an important mission for TCM to propose effective formula with immediate response and solid evidence by using modern biomedical knowledge and techniques(molecular docking assisted TCM formulation for short). In view of the high homology between the gene sequences of the novel coronavirus and SARS virus, and the similarities between the two in terms of pathogenic mechanism and clinical manifestations, our team established a rapid screening and optimization model for the prevention and treatment of the novel coronavirus based on clinical experience and molecular docking technology. Firstly, the clinical team and the research team pre-developed and screened TCM formula by using "back-to-back" manner. Then, the formula was optimized and determined by comparing and analyzing the results of the two groups. The results showed that the research team screened out 46 active ingredients from candidate TCMs that could act on the novel coronavirus S-protein-binding site of human ACE2 protein, which were mainly attributed to 7 herbs such as Lonicerae Japonicae Flos and Mori Folium. The result was largely consistent with the formula raised by the clinical group, verifying and supporting its rationality. This provides evidence for the scientific and potential efficacy of the TCM prescription from the perspective of treatment target analysis, and also suggests that the TCM prescription has the potential to directly inhibit viral infection in addition to improving clinical symptoms or syndromes. Based on this, our team optimized and formed a new anti-coronavirus TCM prescription "Keguan Yihao", immediately providing the TCM prescription with certain clinical experience and objective evidence support for the prevention and treatment of new emergent infectious diseases in our hospital. The TCM prescription was combined with modern medicine symptomatic supportive treatment for clinical treatment, preliminary results showed better effect than symptomatic supportive therapy alone. This research has innovated the method mode in clinical practice and basic research integration of traditional Chinese medicine for the prevention and control of new emerging infectious diseases. It is of great significance to further improve the rapid response mechanism of TCM in face of major epidemics, and further improve the capability level of TCM to prevent and treat new emerging infectious diseases.

HIV-1 infection depletes human CD34+CD38- hematopoietic progenitor cells via pDC-dependent mechanisms.

Chronic human immunodeficiency virus-1 (HIV-1) infection in patients leads to multi-lineage hematopoietic abnormalities or pancytopenia. The deficiency in hematopoietic progenitor cells (HPCs) induced by HIV-1 infection has been proposed, but the relevant mechanisms are poorly understood. We report here that both human CD34+CD38- early and CD34+CD38+ intermediate HPCs were maintained in the bone marrow (BM) of humanized mice. Chronic HIV-1 infection preferentially depleted CD34+CD38- early HPCs in the BM and reduced their proliferation potential in vivo in both HIV-1-infected patients and humanized mice, while CD34+CD38+ intermediate HSCs were relatively unaffected. Strikingly, depletion of plasmacytoid dendritic cells (pDCs) prevented human CD34+CD38- early HPCs from HIV-1 infection-induced depletion and functional impairment and restored the gene expression profile of purified CD34+ HPCs in humanized mice. These findings suggest that pDCs contribute to the early hematopoietic suppression induced by chronic HIV-1 infection and provide a novel therapeutic target for the hematopoiesis suppression in HIV-1 patients.

Clinical Features of Patients With Ebola Virus Disease in Sierra Leone.

BACKGROUND: Clinical and laboratory data available on patients with Ebola virus disease (EVD) remain extremely limited. We summarized the clinical characteristics of patients with EVD and analyzed the factors related to their death. METHODS: Patients admitted for care at the Freetown China-Sierra Leone Friendship Hospital during 1 October-14 November 2014 were enrolled in this study. The clinical data of these patients were retrospectively analyzed. RESULTS: Sixty-one patients were confirmed to have EVD; 28 of them (45.9%) were male and 33 (54.1%) were female. Their median age was 28 years (range, 1.17-67 years). The median duration from symptom onset to clinic visit time was 5 days (range, 1-16 days). Among these patients, 42 of them (68.9%) died. Of the confirmed cases, 18.0% did not present with fever. Patients aged >30 years had a higher fatality rate than those <30 years (87.0% vs 57.9%; P = .0175). The mean duration from symptom onset to clinic presentation of the survivors (4.57 ± 2.79 days) was shorter than that of the nonsurvivors (6.34 ± 3.33 days). Clinical factors associated with a fatal outcome included weakness, extreme fatigue, vomiting, diarrhea, mental symptoms, bleeding, and loss of appetite. No statistical difference in the case fatality rate between males and females was found (P = .2061). CONCLUSIONS: The mortality of patients with EVD was closely associated with age and duration from symptom onset to presentation for care. Patients with EVD identified in the current outbreak did not necessarily have fever. Early diagnosis of the disease and timely symptomatic treatment may greatly contribute to the reduction of fatality rate of patients with EVD.

Cross-sectional study of the relationship of peripheral blood cell profiles with severity of infection by adenovirus type 55.

BACKGROUND: The immunologic profiles of patients with human adenovirus serotype 55 (HAdV-55) infections were characterized in subjects diagnosed with silent infections (n = 30), minor infections (n = 27), severe infections (n = 34), and healthy controls (n = 30) during a recent outbreak among Chinese military trainees. METHODS: Blood was sampled at the disease peak and four weeks later, and samples were analyzed to measure changes in leukocyte and platelet profiles in patients with different severities of disease. Differential lymphocyte subsets and cytokine profiles were measured by flow cytometry and Luminex xMAP®, and serum antibodies were analyzed by ELISA and immunofluorescence staining. RESULTS: Patients with severe HAdV infections had higher proportions of neutrophils and reduced levels of lymphocytes (p < 0.005 for both). Patients with minor and severe infections had significantly lower platelet counts (p < 0.005 for both) than those with silent infections. The silent and minor infection groups had higher levels of dendritic cells than the severe infection group. Relative to patients with silent infections, patients with severe infections had significantly higher levels of IL-17+CD4+ cells, decreased levels of IL-17+CD8+ cells, and higher levels of IFN-γ, IL-4, IL-10, and IFN-α2 (p < 0.001 for all comparisons). CONCLUSIONS: Patients with different severities of disease due to HAdV-55 infection had significantly different immune responses. These data provide an initial step toward the identification of patients at risk for more severe disease and the development of treatments against HAdV-55 infection.

Laboratory features throughout the disease course of influenza A (H1N1) virus infection.

BACKGROUND: Influenza has emerged every year but a complete profile of laboratory indices throughout the disease course remains unknown. METHODS: Clinical data was collected from 28 confirmed cases of the pandemic influenza H1N1 2009. The levels of serum iron (Fe), carbon dioxide combining power (CO2-CP), total complement hemolytic activity (CH50), C-reactive protein (CRP), and white blood cell (WBC) and differential count were analyzed. RESULTS: Major laboratory abnormalities recokled for patients upon admission were lymphopenia (96.4%), eosinopenia (50.0%), hypoferremia (92.9%), decreased levels of serum CO2-CP (60.7%), increased levels of serum CRP (84.6%) and serum CH50 (71.4%). The serum iron and CO2-CP concentration and the counts for lymphocytes, eosinophils, and basophils were significantly increased four days after sickness was noticed compared with the first three days of illness (p < 0.05). The total WBC and neutrophil counts were significantly decreased four days after onset of illness compared with the counts over the first three days (p < 0.05). The monocyte count and CRP concentration was significantly decreased 7 days after onset of illness compared with first 3 days after illness onset (p < 0.05). The serum CH50 concentrations were higher than the normal range during disease course and significantly elevated 7 days after onset of illness compared with the first 6 days after illness onset (p < 0.05). CONCLUSIONS: The serum levels of iron, CO2-CP, CH50, CRP, and WBC and differential count Were significantly varied during the whole pandemic influenza (H1N1) 2009. The development of WBC count in patients with influenza may be an effective predictor for severity of illness.

Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients.

UNLABELLED: Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection. Although NK cells have been implicated in inducing hepatocellular damage in patients with chronic hepatitis virus infections, the roles that hepatic NK cells play in chronic hepatitis B virus (HBV) infections remain obscure. In this study, we comprehensively characterized intrahepatic and peripheral NK cells and investigated their impact on liver pathology in a cohort of HBV-infected individuals; this cohort included 51 immune-activated (IA) patients, 27 immune-tolerant (IT) carriers, and 26 healthy subjects. We found that NK cells expressing NK receptors (activation receptors) preferentially accumulated in the livers of IA patients, in which they were activated and skewed toward cytolytic activity but without a concomitant increase in interferon-γ production, in comparison with those of IT carriers and healthy subjects. Further analysis showed that the livers of IA patients, in comparison with those of IT and healthy subjects, expressed higher levels of interleukin-12 (IL-12), IL-15, and IL-18 in situ and lower levels of IL-10, which in vitro can induce the activation and degranulation of NK cells from healthy individuals. Finally, hepatic NK cells displayed more cytolytic activity than peripheral NK cells, and this was found to be positively correlated with the liver histological activity index and serum alanine aminotransferase levels in these IA patients. CONCLUSION: In IA patients, hepatic NK cells are activated and preferentially skew toward cytolytic activity, which depends on an imbalanced cytokine milieu and correlates with liver injury during chronic HBV infection.

Soluble Receptor for Advanced Glycation End Product Is Involved in the Inflammatory Response of Human Adenovirus-Infected Patients.

Human adenovirus (HAdV) infection causes excessive inflammation associated with severe tissue injury, such as pneumonia. The molecules involved in the underlying inflammatory mechanisms remain to be elucidated. Receptor for advanced glycation end product (RAGE) is mainly expressed on immune cells and lung tissues, and it is a key factor in the initiation and development of inflammation. RAGE can be cleaved by metalloprotease 9 (MMP9) to release the extracellular segment, which is named soluble RAGE (sRAGE), into the intercellular space, where it can bind to RAGE ligands and block RAGE activation and subsequent inflammation. In our study, we enrolled HAdV-infected patients and their contacts to examine the relationship between sRAGE and inflammation induced by HAdV infection. The results showed that HAdV infection stimulated inflammatory cytokine secretion, increased such as high mobility group box 1 (HMGB1) levels, and suppressed sRAGE expression. sRAGE levels were significantly different between patients with or without pneumonia. We also found that MMP9 was significantly lower in patients with pneumonia, and it was positively correlated with sRAGE levels over 7 days after disease onset. The mitogen-activated protein kinase (MAPK) pathway is an important immune activation signaling pathway that is regulated by RAGE. We observed the activation of the MAPK pathway in the peripheral blood mononuclear cells (PBMCs) of patients. Negative correlations between sRAGE and phosphorylated JNK and p38 were observed. These results suggest that sRAGE is involved in HAdV-induced inflammatory responses, and might be a potential therapeutic target to alleviate the HAdV-induced excessive inflammation.

Olfactory and gustatory dysfunctions of COVID-19 patients in China: A multicenter study.

Introduction: With the spread of the epidemic worldwide, an increasing number of doctors abroad have observed the following atypical symptoms of coronavirus disease 2019 (COVID-19): olfactory or taste disorders. Therefore, clarifying the incidence and clinical characteristics of olfactory and taste disorders in Chinese COVID-19 patients is of great significance and urgency. Materials and Methods: A retrospective study was conducted, which included 229 severe acute respiratory syndrome coronavirus 2 confirmed patients, through face-to-face interviews and telephone follow-up. Following the completion of questionnaires, the patients participating in the study, were categorized according to the degree of olfactory and taste disorders experienced, and the proportion of each clinical type of patient with olfactory and taste disorders and the time when symptoms appeared were recorded. Results: Among the 229 patients, 31 (13.54%) had olfactory dysfunction, and 44 (19.21%) had gustatory dysfunction. For the patients with olfactory dysfunction, 6 (19.35%) developed severe disease and became critically ill. Olfactory dysfunction appeared before the other symptoms in 21.43% of cases. The proportion of females with olfactory and gustatory dysfunction was higher than that of males (P < 0.001). Conclusions: The incidence of olfactory and gustatory dysfunction was much lower than that reported abroad; the prognosis of patients with olfactory dysfunction is relatively favorable; olfactory and gustatory dysfunction can be used as a sign for early screening; females are more prone to olfactory and gustatory dysfunction.

Mimotopes selected with neutralizing antibodies against multiple subtypes of influenza A.

BACKGROUND: The mimotopes of viruses are considered as the good targets for vaccine design. We prepared mimotopes against multiple subtypes of influenza A and evaluate their immune responses in flu virus challenged Balb/c mice. METHODS: The mimotopes of influenza A including pandemic H1N1, H3N2, H2N2 and H1N1 swine-origin influenza virus were screened by peptide phage display libraries, respectively. These mimotopes were engineered in one protein as multi- epitopes in Escherichia coli (E. coli) and purified. Balb/c mice were immunized using the multi-mimotopes protein and specific antibody responses were analyzed using hemagglutination inhibition (HI) assay and enzyme-linked immunosorbent assay (ELISA). The lung inflammation level was evaluated by hematoxylin and eosin (HE). RESULTS: Linear heptopeptide and dodecapeptide mimotopes were obtained for these influenza virus. The recombinant multi-mimotopes protein was a 73 kDa fusion protein. Comparing immunized infected groups with unimmunized infected subsets, significant differences were observed in the body weight loss and survival rate. The antiserum contained higher HI Ab titer against H1N1 virus and the lung inflammation level were significantly decreased in immunized infected groups. CONCLUSIONS: Phage-displayed mimotopes against multiple subtypes of influenza A were accessible to the mouse immune system and triggered a humoral response to above virus.

[Diagnostic analysis of hospitalized patients with fever of unknown origin at department of infectious diseases].

OBJECTIVE: To explore the etiology, diagnostic methods and procedures for patients with fever of unknown origin (FUO) at department of infectious diseases. METHODS: A total of 368 FUO patients admitted to department of infectious diseases from 2002 to 2009 were retrospectively reviewed. The correlations of etiologies and diagnostic methods with gender, age and progress of fever were analyzed. RESULTS: Among them, 112 (30.4%) cases were recognized in 2 weeks (diagnosis, n = 107; recovery with unknown causes, n = 5). A final diagnosis was established in 241 (94.1%) from the remaining 256 FUO patients (124 males, 132 females). Among them, the causes were infectious diseases (n = 193), rheumatologic/autoimmune diseases (n = 32) and hematological diseases/tumors (n = 16). The etiologies were infectious diseases (n = 95), rheumatologic/autoimmune diseases (n = 10), hematological diseases/tumors (n = 10) and unknown etiology (n = 9) in males respectively; infectious diseases (n = 98), rheumatologic diseases (n = 22), hematological diseases or tumors (n = 6) and unknown etiology (n = 6) in females respectively. Age of patients: < 14 yr (n = 10), 15 - 20 yr (n = 37), 21 - 50 yr (n = 110), 51 - 60 yr (n = 48) and > 61 yr (n = 51). Thermal process was < 4 weeks (n = 83) including 74 infectious diseases cases and > 8 weeks (n = 63), including infectious diseases (n = 21) and rheumatologic disease (n = 20). CONCLUSION: Some FUO outpatients may be promptly confirmed by history taking, physical examination and routine examinations. The major cause is infection. Other causes of FUO are infectious diseases, rheumatological/autoimmune diseases and hematological diseases/tumors. For the diagnosis of FUO patients, gender, age and thermal process should be considered.

Single-cell epigenomic landscape of peripheral immune cells reveals establishment of trained immunity in individuals convalescing from COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection often causes severe complications and even death. However, asymptomatic infection has also been reported, highlighting the difference in immune responses among individuals. Here we performed single-cell chromatin accessibility and T cell-receptor analyses of peripheral blood mononuclear cells collected from individuals convalescing from COVID-19 and healthy donors. Chromatin remodelling was observed in both innate and adaptive immune cells in the individuals convalescing from COVID-19. Compared with healthy donors, recovered individuals contained abundant TBET-enriched CD16+ and IRF1-enriched CD14+ monocytes with sequential trained and activated epigenomic states. The B-cell lineage in recovered individuals exhibited an accelerated developmental programme from immature B cells to antibody-producing plasma cells. Finally, an integrated analysis of single-cell T cell-receptor clonality with the chromatin accessibility landscape revealed the expansion of putative SARS-CoV-2-specific CD8+ T cells with epigenomic profiles that promote the differentiation of effector or memory cells. Overall, our data suggest that immune cells of individuals convalescing from COVID-19 exhibit global remodelling of the chromatin accessibility landscape, indicative of the establishment of immunological memory.