Blood unconjugated bilirubin and tacrolimus are negative predictors of specific cellular immunity in kidney transplant recipients after SAR-CoV-2 inactivated vaccination.

The immunogenicity of SARS-CoV-2 vaccines is poor in kidney transplant recipients (KTRs). The factors related to poor immunogenicity to vaccination in KTRs are not well defined. Here, observational study demonstrated no severe adverse effects were observed in KTRs and healthy participants (HPs) after first or second dose of SARS-CoV-2 inactivated vaccine. Different from HPs with excellent immunity against SARS-CoV-2, IgG antibodies against S1 subunit of spike protein, receptor-binding domain, and nucleocapsid protein were not effectively induced in a majority of KTRs after the second dose of inactivated vaccine. Specific T cell immunity response was detectable in 40% KTRs after the second dose of inactivated vaccine. KTRs who developed specific T cell immunity were more likely to be female, and have lower levels of total bilirubin, unconjugated bilirubin, and blood tacrolimus concentrations. Multivariate logistic regression analysis found that blood unconjugated bilirubin and tacrolimus concentration were significantly negatively associated with SARS-CoV-2 specific T cell immunity response in KTRs. Altogether, these data suggest compared to humoral immunity, SARS-CoV-2 specific T cell immunity response are more likely to be induced in KTRs after administration of inactivated vaccine. Reduction of unconjugated bilirubin and tacrolimus concentration might benefit specific cellular immunity response in KTRs following vaccination.

Comparison of Target Pocket Similarity and Progress into Research on Inhibitors of Picornavirus 3C Proteases.

The 3C protease (3C Pro) plays a significant role in the life cycle of picornaviruses from replication to translation, making it an attractive target for structure-based design of drugs against picornaviruses. The structurally related 3C-like protease (3CL Pro) is an important protein involved in the replication of coronaviruses. With the emergence of COVID-19 and consequent intensive research into 3CL Pro, development of 3CL Pro inhibitors has emerged as a popular topic. This article compares the similarities of the target pockets of various 3C and 3CL Pros from numerous pathogenic viruses. This article also reports several types of 3C Pro inhibitors that are currently undergoing extensive studies and introduces various structural modifications of 3C Pro inhibitors to provide a reference for the development of new and more effective inhibitors of 3C Pro and 3CL Pro.

Immunity against Delta and Omicron variants elicited by homologous inactivated vaccine booster in kidney transplant recipients.

Background: A third mRNA vaccine booster is recommended to improve immunity against SARS-CoV-2 in kidney transplant recipients (KTRs). However, the immunity against SARS-CoV-2 Ancestral strain and Delta and Omicron variants elicited by the third dose of inactivated booster vaccine in KTRs remains unknown. Methods: The blood parameters related to blood cells count, hepatic function, kidney function, heart injury and immunity were explored clinically from laboratory examinations. SARS-CoV-2 specific antibody IgG titer was detected using an enzyme-linked immunosorbent assay. Cellular immunity was analyzed using interferon-γ enzyme-linked immunospot assay. Results: The results showed that there were no severe adverse effects and apparent changes of clinical laboratory biomarkers in KTRs and healthy volunteers (HVs) after homologous inactivated vaccine booster. A third dose of inactivated vaccine booster significantly increased anti-Ancestral-spike-trimer-IgG and anti-Ancestral-receptor binding domain (RBD)-IgG titers in KTRs and HVs compared with the second vaccination. However, the anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG titers were significantly lower than anti-Ancestral-RBD-IgG titer in KTRs and HVs after the third dose. Notably, only 25.6% (10/39) and 10.3% (4/39) of KTRs had seropositivity for anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG after booster, which were significantly lower than HVs (anti-Delta-RBD-IgG: 100%, anti-Omicron-RBD-IgG: 77.8%). Ancestral strain nucleocapsid protein and spike specific T cell frequency after booster was not significantly increased in KTRs compared with the second dose, significantly lower than that in HVs. Moreover, 33.3% (12/36), 14.3% (3/21) and 14.3% (3/21) of KTRs were positive for the Ancestral strain and Delta and Omicron spike-specific T cells, which were significantly lower than HVs (Ancestral: 80.8%, Delta: 53.8%, and Omicron: 57.7%). Conclusions: A third dose of inactivated booster vaccine may significantly increase humoral immunity against the Ancestral strain in KTRs, while humoral and cellular immunity against the Delta and Omicron variants were still poor in KTRs.

Ad5-nCoV booster and Omicron variant breakthrough infection following two doses of inactivated vaccine elicit comparable antibody levels against Omicron variants.

Little information is available for antibody levels against SARS-CoV-2 variants of concern induced by Omicron breakthrough infection and a third booster with an inactivated vaccine (InV) or Ad5-nCoV in people with completion of two InV doses. Plasma was collected from InV pre-vaccinated Omicron-infected patients (OIPs), unvaccinated OIPs between 0 and 22 days, and healthy donors (HDs) 14 days or 6 months after the second doses of an InV and 14 days after a homogenous booster or heterologous booster of Ad5-nCoV. Anti-Wuhan-, Anti-Delta-, and Anti-Omicron-receptor binding domain (RBD)-IgG titers were detected using enzyme-linked immunosorbent assay. InV pre-vaccinated OIPs had higher anti-Wuhan-, anti-Delta-, and anti-Omicron-RBD-IgG titers compared to unvaccinated OIPs. Anti-Wuhan-RBD-IgG titers sharply increased in InV pre-vaccinated OIPs 0-5 days postinfection (DPI), while the geometric mean titers (GMTs) of anti-Delta- and anti-Omicron-RBD-IgG were 3.3-fold and 12.0-fold lower. Then, the GMT of anti-Delta- and anti-Omicron-RBD-IgG increased to 35 112 and 28 186 during 11-22 DPI, about 2.6-fold and 3.2-fold lower, respectively, than the anti-Wuhan-RBD-IgG titer. The anti-Wuhan-, anti-Delta-, and anti-Omicron-RBD-IgG titers declined over time in HDs after two doses of an InV, with 25.2-fold, 5.6-fold, and 4.5-fold declination, respectively, at 6 months relative to the titers at 14 days after the second vaccination. Anti-Wuhan-, anti-Delta-, and anti-Omicron-RBD-IgG titers elicited by a heterologous Ad5-nCoV booster were significantly higher than those elicited by an InV booster, comparable to those in InV pre-vaccinated OIPs. InV and Ad5-nCoV boosters could improve humoral immunity against Omicron variants. Of these, the Ad5-nCoV booster is a better alternative.

Immunity against Delta and Omicron variants elicited by homologous inactivated vaccine booster in kidney transplant recipients

Background A third mRNA vaccine booster is recommended to improve immunity against SARS-CoV-2 in kidney transplant recipients (KTRs). However, the immunity against SARS-CoV-2 Ancestral strain and Delta and Omicron variants elicited by the third dose of inactivated booster vaccine in KTRs remains unknown. Methods The blood parameters related to blood cells count, hepatic function, kidney function, heart injury and immunity were explored clinically from laboratory examinations. SARS-CoV-2 specific antibody IgG titer was detected using an enzyme-linked immunosorbent assay. Cellular immunity was analyzed using interferon-γ enzyme-linked immunospot assay. Results The results showed that there were no severe adverse effects and apparent changes of clinical laboratory biomarkers in KTRs and healthy volunteers (HVs) after homologous inactivated vaccine booster. A third dose of inactivated vaccine booster significantly increased anti-Ancestral-spike-trimer-IgG and anti-Ancestral-receptor binding domain (RBD)-IgG titers in KTRs and HVs compared with the second vaccination. However, the anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG titers were significantly lower than anti-Ancestral-RBD-IgG titer in KTRs and HVs after the third dose. Notably, only 25.6% (10/39) and 10.3% (4/39) of KTRs had seropositivity for anti-Delta-RBD-IgG and anti-Omicron-RBD-IgG after booster, which were significantly lower than HVs (anti-Delta-RBD-IgG: 100%, anti-Omicron-RBD-IgG: 77.8%). Ancestral strain nucleocapsid protein and spike specific T cell frequency after booster was not significantly increased in KTRs compared with the second dose, significantly lower than that in HVs. Moreover, 33.3% (12/36), 14.3% (3/21) and 14.3% (3/21) of KTRs were positive for the Ancestral strain and Delta and Omicron spike-specific T cells, which were significantly lower than HVs (Ancestral: 80.8%, Delta: 53.8%, and Omicron: 57.7%). Conclusions A third dose of inactivated booster vaccine may significantly increase humoral immunity against the Ancestral strain in KTRs, while humoral and cellular immunity against the Delta and Omicron variants were still poor in KTRs.

Omicron variants breakthrough infection elicited higher specific memory immunity than third dose booster in healthy vaccinees.

Homologous booster, heterologous booster, and Omicron variants breakthrough infection (OBI) could improve the humoral immunity against Omicron variants. Questions concerning about memory B cells (MBCs) and T cells immunity against Omicron variants, features of long-term immunity, after booster and OBI, needs to be explored. Here, comparative analysis demonstrate antibody and T cell immunity against ancestral strain, Delta and Omicron variants in Omicron breakthrough infected patients (OBIPs) are comparable to that in Ad5-nCoV boosted healthy volunteers (HVs), higher than that in inactivated vaccine (InV) boosted HVs. However, memory B cells (MBCs) immunity against Omicron variants was highest in OBIPs, followed by Ad5-nCoV boosted and InV boosted HVs. OBIPs and Ad5-nCoV boosted HVs have higher classical MBCs and activated MBCs, and lower naïve MBCs and atypical MBCs relative to both vaccine boosted HVs. Collectively, these data indicate Omicron breakthrough infection elicit higher MBCs and T cells against SARS-CoV-2 especially Omicron variants relative to homologous InV booster and heterologous Ad5-nCoV booster.

Use of radiolabeled hyaluronic acid for preclinical assessment of inflammatory injury and acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system. METHODS: HA of 10 kDa molecular weight (HA10) was radiolabeled with 125I and 99mTc respectively to produce [125I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS. RESULTS: [99mTc]Tc-HA10 and [125I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining. CONCLUSIONS: [99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS.

Use of radiolabeled hyaluronic acid for preclinical assessment of inflammatory injury and acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system. Methods HA of 10 kDa molecular weight (HA10) was radiolabeled with 125I and 99mTc respectively to produce [125I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS. Results [99mTc]Tc-HA10 and [125I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining. Conclusions [99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS. Graphical Unlabelled Image

Human adenovirus (HAdV) infection in children with acute respiratory tract infections in Guangzhou, China, 2010-2021: a molecular epidemiology study.

BACKGROUND: Human adenovirus (HAdV) infection can cause a variety of diseases. It is a major pathogen of pediatric acute respiratory tract infections (ARIs) and can be life-threatening in younger children. We described the epidemiology and subtypes shifting of HAdV among children with ARI in Guangzhou, China. METHODS: We conducted a retrospective study of 161,079 children diagnosed with acute respiratory illness at the Guangzhou Women and Children's Medical Center between 2010 and 2021. HAdV specimens were detected by real-time PCR and the hexon gene was used for phylogenetic analysis. RESULTS: Before the COVID-19 outbreak in Guangzhou, the annual frequency of adenovirus infection detected during this period ranged from 3.92% to 13.58%, with an epidemic peak every four to five years. HAdV demonstrated a clear seasonal distribution, with the lowest positivity in March and peaking during summer (July or August) every year. A significant increase in HAdV cases was recorded for 2018 and 2019, which coincided with a shift in the dominant HAdV subtype from HAdV-3 to HAdV-7. The latter was associated with a more severe disease compared to HAdV-3. The average mortality proportion for children infected with HAdV from 2016 to 2019 was 0.38% but increased to 20% in severe cases. After COVID-19 emerged, HAdV cases dropped to 2.68%, suggesting that non-pharmaceutical interventions probably reduced the transmission of HAdV in the community. CONCLUSION: Our study provides the foundation for the understanding of the epidemiology of HAdV and its associated risks in children in Southern China.

Thrombocytopenia and increased risk of adverse outcome in COVID-19 patients.

Background: Thrombocytopenia was common in the coronavirus disease 2019 (COVID-19) patients during the infection, while the role of thrombocytopenia in COVID-19 pathogenesis and its relationship with systemic host response remained obscure. The study aimed to systematically evaluate the relationship between thrombocytopenia in COVID-19 patients and clinical, haematological and biochemical markers of the disease as well as adverse outcomes. Methods: To assess the relationship between abnormal platelet levels and disease progression, a multi-center retrospective cohort study was conducted. COVID-19 patients with thrombocytopenia and a sub-cohort of matched patients without thrombocytopenia were compared for their clinical manifestations, haematological disorders, biochemical parameters, inflammatory markers and clinical outcome. Results: Thrombocytopenia was present in 127 of 2,209 analyzed patients on admission. Compared with the control group, thrombocytopenia patients developed significantly higher frequency of respiratory failure (41.9% vs. 22.6%, P = 0.020), intensive care unit entrance (25.6% vs. 11.5%, P = 0.012), disseminated intravascular coagulation (45.2% vs. 10.6%, P < 0.001), more altered platelet morphology indexes and coagulation perturbation, higher levels of inflammatory markers. In addition, a significantly increased all-cause mortality (hazard ratio 3.08, 95% confidence interval 2.26-4.18, P < 0.001) was also observed in the patients with thrombocytopenia. Late development of thrombocytopenia beyond 14 days post-symptom was observed in 61 patients, from whom a comparable mortality rate yet longer duration to death was observed compared to those with early thrombocytopenia. Conclusions: Our finding from this study adds to previous evidence that thrombocytopenia is associated with adverse outcome of the disease and recommend that platelet count and indices be included alongside other haematological, biochemical and inflammatory markers in COVID-19 patients' assessment during the hospital stay.

Serum Unconjugated Bilirubin as a Predictor of Specific Cellular Immunity Response in Kidney Transplant Recipients after Administration of SARS-CoV-2 Inactivated Vaccine (preprint)

Purpose: The immunogenicity of SARS-CoV-2 vaccines is poor in kidney transplant recipients (KTRs). The factors related to poor immunogenicity to vaccination in KTRs are not well defined. Methods An observational study was conducted in KTRs and healthy individuals who had received two doses of SARS-CoV-2 inactivated vaccine. IgG antibodies against the receptor-binding domain found in the S1 subunit of the spike protein, and against nucleocapsid protein were measured using enzyme-linked immunosorbent assay. Receptor-binding domain (RBD)-angiotensin-converting enzyme 2 interaction-blocking antibodies were measured using commercial kits. T cell responses against the spike and nucleocapsid proteins were detected using enzyme-linked immunosorbent spot assay. Results No severe adverse effects were observed in KTRs after first or second dose of SARS-CoV-2 inactivated vaccine. IgG antibodies against the receptor- binding domain, and nucleocapsid protein were not effectively induced in a majority of KTRs after second dose of inactivated vaccine. Specific T cell immunity response was detectable in 32%-40% KTRs after second doses of inactivated vaccine. KTRs who developed specific T cell immunity were more likely to be female, and have lower levels of total bilirubin, unconjugated bilirubin, and blood tacrolimus concentration. Multivariate logistic regression analysis found that blood unconjugated bilirubin was significantly negatively associated with SARS-CoV-2 specific T cell immunity response in k KTRs. Conclusions Specific T cell immunity response could be induced in 32%-40% KTRs after two doses of inactivated vaccine. Blood unconjugated bilirubin was negatively associated with specific cellular immunity response in KTRs following vaccination.

Pain during and after coronavirus disease 2019: Chinese perspectives.

The coronavirus disease 2019 (COVID-19) global pandemic poses a major threat to human health and health care systems. Urgent prevention and control measures have obstructed patients' access to pain treatment, and many patients with pain have been unable to receive adequate and timely medical services. Many patients with COVID-19 report painful symptoms including headache, muscle pain, and chest pain during the initial phase of the disease. Persistent pain sequela in patients with COVID-19 has a physical or mental impact and may also affect the immune, endocrine, and other systems. However, the management and treatment of neurological symptoms such as pain are often neglected for patients hospitalized with COVID-19. Based on the China's early experience in the management of COVID-19 symptoms, the possible negative effects of pre-existing chronic pain in patients with COVID-19 and the challenges of COVID-19 prevention and control bring to the diagnosis and treatment of chronic pain are discussed. This review calls to attention the need to optimize pain management during and after COVID-19.

Linking the gut microbiota to persistent symptoms in survivors of COVID-19 after discharge.

Several follow-up studies have found that COVID-19 (coronavirus disease 2019) patients had persistent symptoms after discharge. Gut microbiota play an important role in human health and immune responses. Therefore, this study investigated the gut microbiota of recovered COVID-19 patients and the correlations between gut microbiota and persistent symptoms after discharge. Stool samples were collected from 15 recovered healthcare workers (HCWs) with COVID-19 at three months after discharge, in addition, stool samples were collected from 14 healthy controls (HCs) to perform 16S rRNA gene sequencing between May and July 2020. Compared with HCs, recovered HCWs had reduced bacterial diversity at three months after discharge, with a significantly higher relative abundance of opportunistic pathogens, and a significantly lower relative abundance of beneficial bacteria. In addition, Escherichia unclassified was positively correlated with persistent symptoms at three months after discharge, including fatigue (r = 0.567, p = 0.028), chest tightness after activity (r = 0.687, p = 0.005), and myalgia (r = 0.523, p = 0.045). Intestinibacter bartlettii was positively correlated with anorexia (r = 0.629, p = 0.012) and fatigue (r = 0.545, p = 0.036). However, Faecalibacterium prausnitzii was negatively correlated with chest tightness after activity (r = -0.591, p = 0.02), and Intestinimonas butyriciproducens was negatively correlated with cough (r = -0.635, p = 0.011). In conclusion, the gut microbiota of recovered HCWs with COVID-19 at three months after discharge was different from that of HCs, and altered gut microbiota was correlated with persistent symptoms after discharge, highlighting that gut microbiota may play an important role in the recovery of patients with COVID-19.

Prolonged SARS-CoV-2 Viral Shedding in Patients with COVID-19 was Associated with Delayed Initiation of Arbidol Treatment and Consulting Doctor Later: A Retrospective Cohort Study.

OBJECTIVE: To study data about SARS-CoV-2 virus shedding and clarify the risk factors for prolonged virus shedding. METHODS: Data were retrospectively collected from adults hospitalized with laboratory-confirmed coronavirus disease-19 (COVID-19) in Wuhan Union Hospital. We compared clinical features among patients with prolonged (a positive SARS-CoV-2 RNA on day 23 after illness onset) and short virus shedding and evaluated risk factors associated with prolonged virus shedding by multivariate regression analysis. RESULTS: Among 238 patients, the median age was 55.5 years, 57.1% were female, 92.9% (221/238) were administered with arbidol, 58.4% (139/238) were given arbidol in combination with interferon. The median duration of SARS-CoV-2 virus shedding was 23 days (IQR, 17.8-30 days) with a longest one of 51 days. The patients with prolonged virus shedding had higher value of D-dimer (P=0.002), IL-6 (P<0.001), CRP (P=0.005) and more lobes lung lesion (P=0.014) on admission, as well as older age (P=0.017) and more patients with hypertension (P=0.044) than in those the virus shedding less than 23 days. Multivariate regression analysis revealed that prolonged viral shedding was significantly associated with initiation arbidol >8 days after symptom onset [OR: 2.447, 95% CI (1.351-4.431)], ≥3 days from onset of symptoms to first medical visitation [OR: 1.880, 95% CI (1.035-3.416)], illness onset before Jan. 31, 2020 [OR: 3.289, 95% CI (1.474-7.337)]. Arbidol in combination with interferon was also significantly associated with shorter virus shedding [OR: 0.363, 95% CI (0.191-0.690)]. CONCLUSION: Duration of SARS-CoV-2 virus shedding was long. Early initiation of arbidol and arbidol in combination with interferon as well as consulting doctor timely after illness onset were helpful for SARS-CoV-2 clearance.

Neurological manifestations in COVID-19 patients and their application in predicting fatal disease: A retrospective cohort study.

BACKGROUND: To explore the development of central nervous system (CNS) symptoms and clinical application in predicting the clinical outcomes of SARS-COV-2 patients. METHODS: A retrospective cohort study was performed on the hospitalized patients with SARS-COV-2 recruited from four hospitals in Hubei Province, China from 18 January to 10 March 2020. The patients with CNS symptoms were determined. Data regarding clinical symptoms and laboratory tests were collected from medical records. RESULTS: Of 1268 patients studied, 162 (12.8%) had CNS symptoms, manifested as unconsciousness (71, 5.6%), coma (69, 5.4%), dysphoria (50, 3.9%), somnolence (34, 2.7%) and convulsion (3, 0.2%), which were observed at median of 14 (interquartile range 9-18) days after symptom onset and significantly associated with older age (OR = 5.71, 95% confidence interval [CI] 2.78-11.73), male (OR = 1.73, 95% CI 1.22-2.47) and preexisting hypertension (OR = 1.78, 95% CI 1.23-2.57). The presence of CNS symptoms could be predicted by abnormal laboratory tests across various clinical stages, including by lymphocyte counts of <0.93 × 109/L, LDH≥435 U/L and IL-6≥28.83 pg/L at 0-10 days post disease; by lymphocyte count<0.86 × 109/L, IL-2R ≥ 949 U/L, LDH≥382 U/L and WBC≥8.06 × 109/L at 11-20 days post disease. More patients with CNS symptoms developed fatal outcome compared with patients without CNS symptoms (HR = 33.96, 95% CI 20.87-55.16). CONCLUSION: Neurological symptoms of COVID-19 were related to increased odds of developing poor prognosis and even fatal infection.

Laboratory Predictors of COVID-19 Pneumonia in Patients with Mild to Moderate Symptoms.

OBJECTIVE: This research aims to develop a laboratory model that can accurately distinguish pneumonia from nonpneumonia in patients with COVID-19 and to identify potential protective factors against lung infection. METHODS: We recruited 50 patients diagnosed with COVID-19 infection with or without pneumonia. We selected candidate predictors through group comparison and punitive least absolute shrinkage and selection operator (LASSO) analysis. A stepwise logistic regression model was used to distinguish patients with and without pneumonia. Finally, we used a decision-tree method and randomly selected 50% of the patients 1000 times from the same specimen to verify the effectiveness of the model. RESULTS: We found that the percentage of eosinophils, a high-fluorescence-reticulocyte ratio, and creatinine had better discriminatory power than other factors. Age and underlying diseases were not significant for discrimination. The model correctly discriminated 77.1% of patients. In the final validation step, we observed that the model had an overall predictive rate of 81.3%. CONCLUSION: We developed a laboratory model for COVID-19 pneumonia in patients with mild to moderate symptoms. In the clinical setting, the model will be able to predict and differentiate pneumonia vs nonpneumonia before any lung computed tomography findings. In addition, the percentage of eosinophils, a high-fluorescence-reticulocyte ratio, and creatinine were considered protective factors against lung infection in patients without pneumonia.

Gut Microbiota Dysbiosis Correlates with Abnormal Immune Response in Moderate COVID-19 Patients with Fever.

BACKGROUND: Most COVID-19 patients are moderate, and fever is the most common clinical manifestation and associated with poorer prognosis. Gut microbiota may also play important roles in COVID-19 pathogenesis. However, the association between gut microbiota and fever in individuals with moderate COVID-19 remains unclear. METHODS: We compared the clinical features and laboratory results of 187 moderate COVID-19 patients with fever and without fever and identified several inflammatory markers in patients with fever. Then, we performed gut metagenome-wide association study for 31 individuals to identify the microbes and their epitopes which have potential role in fever and hyperinflammation. RESULTS: Among 187 moderate COVID-19 patients, 127 (67.9%) patients presented with fever. Lymphocytes, CD3+ T cells, CD4+ T cells and the ratio of CD4+ T cells to CD8+ T cells were significantly reduced, while AST, LDH, CRP, IL-6 and IL-10 were significantly elevated in patients with fever. Gut microbiome composition was significantly altered in patients with fever compared with those with non-fever. Opportunistic pathogens such as Enterococcus faecalis and Saccharomyces cerevisiae were enriched in patients with fever. E. faecalis was positively correlated with LDH and D-dimer and negatively correlated with CD8+T cells and IL-4, while S. cerevisiae was positively correlated with diarrhea symptom. Furthermore, several species with anti-inflammatory and protective effects, such as Bacteroides fragilis and Eubacterium ramulus, were enriched in patients with non-fever. B. fragilis was positively correlated with lymphocytes, and E. ramulus was negatively correlated with LDH, AST and IL-6. Finally, we found that several bacterial epitopes of GroEL, a homolog of human HSP60, were enriched in patients with fever and positively correlated with IL-6, IL-10, WBC, neutrophils, D-dimer, LDH, CRP, and E. faecalis. CONCLUSION: Gut microbiota dysbiosis correlates with abnormal immune response in moderate COVID-19 patients with fever.

The differential demographic pattern of coronavirus disease 2019 fatality outside Hubei and from six hospitals in Hubei, China: a descriptive analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic has been largely controlled in China, to the point where case fatality rate (CFR) data can be comprehensively evaluated. METHODS: Data on confirmed patients, with a final outcome reported as of 29 March 2020, were obtained from official websites and other internet sources. The hospitalized CFR (HCFR) was estimated, epidemiological features described, and risk factors for a fatal outcome identified. RESULTS: The overall HCFR in China was estimated to be 4.6% (95% CI 4.5-4.8%, P < 0.001). It increased with age and was higher in males than females. Although the highest HCFR observed was in male patients ≥70 years old, the relative risks for death outcome by sex varied across age groups, and the greatest HCFR risk ratio for males vs. females was shown in the age group of 50-60 years, higher than age groups of 60-70 and ≥ 70 years. Differential age/sex HCFR patterns across geographical regions were found: the age effect on HCFR was greater in other provinces outside Hubei than in Wuhan. An effect of longer interval from symptom onset to admission was only observed outside Hubei, not in Wuhan. By performing multivariate analysis and survival analysis, the higher HCFR was associated with older age (both P < 0.001), and male sex (both P < 0.001). Only in regions outside Hubei, longer interval from symptom onset to admission, were associated with higher HCFR. CONCLUSIONS: This up-to-date and comprehensive picture of COVID-19 HCFR and its drivers will help healthcare givers target limited medical resources to patients with high risk of fatality.