Single-cell analysis of COVID-19, sepsis, and HIV infection reveals hyperinflammatory and immunosuppressive signatures in monocytes.

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients.

Extracorporeal Membrane Oxygenation for SARS-CoV-2 Acute Respiratory Distress Syndrome: A Retrospective Study From Hubei, China.

Background: The data on long-term outcomes of patients infected by SARS-CoV-2 and treated with extracorporeal membrane oxygenation (ECMO) in China are merely available. Methods: A retrospective study included 73 patients infected by SARS-CoV-2 and treated with ECMO in 21 intensive care units in Hubei, China. Data on demographic information, clinical features, laboratory tests, ECMO durations, complications, and living status were collected. Results: The 73 ECMO-treated patients had a median age of 62 (range 33-78) years and 42 (63.6%) were males. Before ECMO initiation, patients had severe respiratory failure on mechanical ventilation with a median PO2/FiO2 of 71.9 [interquartile range (IQR), 58.6-87.0] mmHg and a median PCO2 of 62 [IQR, 43-84] mmHg on arterial blood analyses. The median duration from symptom onset to invasive mechanical ventilation, and to ECMO initiation was19 [IQR, 15-25] days, and 23 [IQR, 19-31] days. Before and after ECMO initiation, the proportions of patients receiving prone position ventilation were 58.9 and 69.9%, respectively. The median duration of ECMO support was 18.5 [IQR 12-30] days. During the treatments with ECMO, major hemorrhages occurred in 31 (42.5%) patients, and oxygenators were replaced in 21 (28.8%) patients. Since ECMO initiation, the 30-day mortality and 60-day mortality were 63.0 and 80.8%, respectively. Conclusions: In Hubei, China, the ECMO-treated patients infected by SARS-CoV-2 were of a broad age range and with severe hypoxemia. The durations of ECMO support, accompanied with increased complications, were relatively long. The long-term mortality in these patients was considerably high.

Early identification of patients with severe COVID-19 at increased risk of in-hospital death: a multicenter case-control study in Wuhan.

BACKGROUND: Most evidence regarding the risk factors for early in-hospital mortality in patients with severe COVID-19 focused on laboratory data at the time of hospital admission without adequate adjustment for confounding variables. A multicenter, age-matched, case-control study was therefore designed to explore the dynamic changes in laboratory parameters during the first 10 days after admission and identify early risk indicators for in-hospital mortality in this patient cohort. METHODS: Demographics and clinical data were extracted from the medical records of 93 pairs of patients who had been admitted to hospital with severe COVID-19. These patients had either been discharged or were deceased by March 3, 2020. Data from days 1, 4, 7, and 10 of hospital admission were compared between survivors and non-survivors. Univariate and multivariate conditional logistic regression analyses were employed to identify early risk indicators of in-hospital death in this cohort. RESULTS: On admission, in-hospital mortality was associated with five risk indicators (ORs in descending order): aspartate aminotransferase (AST, >32 U/L) 43.20 (95% CI: 2.63, 710.04); C-reactive protein (CRP) greater than 100 mg/L 13.61 (1.78, 103.941); lymphocyte count lower than 0.6×109/L 9.95 (1.30, 76.42); oxygen index (OI) less than 200 8.23 (1.04, 65.15); and D-dimer over 1 mg/L 8.16 (1.23, 54.34). Sharp increases in D-dimer at day 4, accompanied by decreasing lymphocyte counts, deteriorating OI, and persistent remarkably high CRP concentration were observed among non-survivors during the early stages of hospital admission. CONCLUSIONS: The potential risk factors of high D-dimer, CRP, AST, low lymphocyte count and OI could help clinicians identify patients at high risk of death early in the hospital admission. This might assist with rationalization of health care resources.

Tracheostomy in 80 COVID-19 Patients: A Multicenter, Retrospective, Observational Study.

Background: The outbreak of coronavirus disease 2019 (COVID-19) has led to a large and increasing number of patients requiring prolonged mechanical ventilation and tracheostomy. The indication and optimal timing of tracheostomy in COVID-19 patients are still unclear, and the outcomes about tracheostomy have not been extensively reported. We aimed to describe the clinical characteristics and outcomes of patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who underwent elective tracheostomies. Methods: The multi-center, retrospective, observational study investigated all the COVID-19 patients who underwent elective tracheostomies in intensive care units (ICUs) of 23 hospitals in Hubei province, China, from January 8, 2020 to March 25, 2020. Demographic information, clinical characteristics, treatment, details of the tracheostomy procedure, successful weaning after tracheostomy, and living status were collected and analyzed. Data were compared between early tracheostomy patients (tracheostomy performed within 14 days of intubation) and late tracheostomy patients (tracheostomy performed after 14 days). Results: A total of 80 patients were included. The median duration from endotracheal intubation to tracheostomy was 17.5 [IQR 11.3-27.0] days. Most tracheotomies were performed by ICU physician [62 (77.5%)], and using percutaneous techniques [63 (78.8%)] at the ICU bedside [76 (95.0%)]. The most common complication was tracheostoma bleeding [14 (17.5%)], and major bleeding occurred in 4 (5.0%) patients. At 60 days after intubation, 31 (38.8%) patients experienced successful weaning from ventilator, 17 (21.2%) patients discharged from ICU, and 43 (53.8%) patients had died. Higher 60 day mortality [22 (73.3%) vs. 21 (42.0%)] were identified in patients who underwent early tracheostomy. Conclusions: In patients with SARS-CoV-2 pneumonia, tracheostomies were feasible to conduct by ICU physician at bedside with few major complications. Compared with tracheostomies conducted after 14 days of intubation, tracheostomies within 14 days were associated with an increased mortality rate.

Characteristics of Liver Function in Patients With SARS-CoV-2 and Chronic HBV Coinfection.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) is a major global health threat. We aimed to describe the characteristics of liver function in patients with SARS-CoV-2 and chronic hepatitis B virus (HBV) coinfection. METHODS: We enrolled all adult patients with SARS-CoV-2 and chronic HBV coinfection admitted to Tongji Hospital from February 1 to February 29, 2020. Data of demographic, clinical characteristics, laboratory tests, treatments, and clinical outcomes were collected. The characteristics of liver function and its association with the severity and prognosis of disease were described. RESULTS: Of the 105 patients with SARS-CoV-2 and chronic HBV coinfection, elevated levels of liver test were observed in several patients at admission, including elevated levels of alanine aminotransferase (22, 20.95%), aspartate aminotransferase (29, 27.62%), total bilirubin (7, 6.67%), gamma-glutamyl transferase (7, 6.67%), and alkaline phosphatase (1, 0.95%). The levels of the indicators mentioned above increased substantially during hospitalization (all P < .05). Fourteen (13.33%) patients developed liver injury. Most of them (10, 71.43%) recovered after 8 (range 6-21) days. Notably the other, 4 (28.57%) patients rapidly progressed to acute-on-chronic liver failure. The proportion of severe COVID-19 was higher in patients with liver injury (P = .042). Complications including acute-on-chronic liver failure, acute cardiac injury and shock happened more frequently in patients with liver injury (all P < .05). The mortality was higher in individuals with liver injury (28.57% vs 3.30%, P = .004). CONCLUSION: Liver injury in patients with SARS-CoV-2 and chronic HBV coinfection was associated with severity and poor prognosis of disease. During the treatment of COVID-19 in chronic HBV-infected patients, liver function should be taken seriously and evaluated frequently.

Coagulopathy of Patients with COVID-19 is Associated with Infectious and Inflammatory Markers.

BACKGROUND: SARS-CoV-2 infection activates coagulation and stimulates innate immune system. Little is known about coagulopathy and response of inflammation and infection in ICU patients with COVID-19. Derangement of coagulation and markers of infection and inflammation induced by SARS-CoV-2 infection, as well as their correlations were elucidated. METHODS: One hundred eight ICU patients with COVID-19 (28 survivors and 80 non-survivors) in Tongji hospital and Wuhan Jinyintan hospital, in Wuhan, China were included. Coagulation parameters, infectious and inflammatory markers were dynamically analysed. The correlation between coagulopathy of patients and infectious and inflammatory markers was verified. RESULTS: SARS-CoV-2-associated coagulopathy occurred in most cases of critical illness. Raised values of d-dimer and FDP were measured in all patients, especially in non-survivors, who had longer PT, APTT, INR, as well as TT, and lower PTA and AT compared to survivors. SIC and DIC mostly occurred in non-survivors. CRP, ESR, serum ferritin, IL-8, and IL-2R increased in all patients, and were much higher in non-survivors who had significantly higher levels of IL-6 and IL-10. D-dimer was positively associated with CRP, serum ferritin (p = 0.02), PCT (p < 0.001), and IL-2R (p = 0.007). SIC scores were positively correlated with CRP (p = 0.006), PCT (p = 0.0007), IL-1ß (p = 0.048), and IL-6 (p = 0.009). DIC scores were positively associated with CRP (p < 0.0001), ESR (p = 0.02), PCT (p < 0.0001), serum ferritin (p < 0.0001), IL-10 (p = 0.02), and IL-2R (p = 0.0005). CONCLUSION: Prothrombotic state, SIC, and DIC are the characteristics of coagulation in ICU patients with COVID-19. CRP, ESR, serum ferritin, IL-8, IL-2R, IL-6, and PCT were stimulated by SARS-CoV-2 infection. CRP, PCT, serum ferritin, and IL-2R indicate the coagulopathy severity of patients with COVID-19.

Acute Physiology and Chronic Health Evaluation II Score as a Predictor of Hospital Mortality in Patients of Coronavirus Disease 2019.

OBJECTIVES: Coronavirus disease 2019 has emerged as a major global health threat with a great number of deaths in China. We aimed to assess the association between Acute Physiology and Chronic Health Evaluation II score and hospital mortality in patients with coronavirus disease 2019, and to compare the predictive ability of Acute Physiology and Chronic Health Evaluation II score, with Sequential Organ Failure Assessment score and Confusion, Urea, Respiratory rate, Blood pressure, Age 65 (CURB65) score. DESIGN: Retrospective observational cohort. SETTING: Tongji Hospital in Wuhan, China. SUBJECTS: Confirmed patients with coronavirus disease 2019 hospitalized in the ICU of Tongji hospital from January 10, 2020, to February 10, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 178 potentially eligible patients with symptoms of coronavirus disease 2019, 23 patients (12.92%) were diagnosed as suspected cases, and one patient (0.56%) suffered from cardiac arrest immediately after admission. Ultimately, 154 patients were enrolled in the analysis and 52 patients (33.77%) died. Mean Acute Physiology and Chronic Health Evaluation II score (23.23 ± 6.05) was much higher in deaths compared with the mean Acute Physiology and Chronic Health Evaluation II score of 10.87 ± 4.40 in survivors (p < 0.001). Acute Physiology and Chronic Health Evaluation II score was independently associated with hospital mortality (adjusted hazard ratio, 1.07; 95% CI, 1.01-1.13). In predicting hospital mortality, Acute Physiology and Chronic Health Evaluation II score demonstrated better discriminative ability (area under the curve, 0.966; 95% CI, 0.942-0.990) than Sequential Organ Failure Assessment score (area under the curve, 0.867; 95% CI, 0.808-0.926) and CURB65 score (area under the curve, 0.844; 95% CI, 0.784-0.905). Based on the cut-off value of 17, Acute Physiology and Chronic Health Evaluation II score could predict the death of patients with coronavirus disease 2019 with a sensitivity of 96.15% and a specificity of 86.27%. Kaplan-Meier analysis showed that the survivor probability of patients with coronavirus disease 2019 with Acute Physiology and Chronic Health Evaluation II score less than 17 was notably higher than that of patients with Acute Physiology and Chronic Health Evaluation II score greater than or equal to 17 (p < 0.001). CONCLUSIONS: Acute Physiology and Chronic Health Evaluation II score was an effective clinical tool to predict hospital mortality in patients with coronavirus disease 2019 compared with Sequential Organ Failure Assessment score and CURB65 score. Acute Physiology and Chronic Health Evaluation II score greater than or equal to 17 serves as an early warning indicator of death and may provide guidance to make further clinical decisions.

The laboratory tests and host immunity of COVID-19 patients with different severity of illness.

BACKGROUNDThe coronavirus disease 2019 (COVID-19), infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a severe outbreak throughout the world. The host immunity of COVID-19 patients is unknown.METHODSThe routine laboratory tests and host immunity in COVID-19 patients with different severity of illness were compared after patient admission.RESULTSA total of 65 SARS-CoV-2-positive patients were classified as having mild (n = 30), severe (n = 20), and extremely severe (n = 15) illness. Many routine laboratory tests, such as ferritin, lactate dehydrogenase, and D-dimer, were increased in severe and extremely severe patients. The absolute numbers of CD4+ T cells, CD8+ T cells, and B cells were gradually decreased with increased severity of illness. The activation markers such as HLA-DR and CD45RO expressed on CD4+ and CD8+ T cells were increased in severe and extremely severe patients compared with mild patients. The costimulatory molecule CD28 had opposite results. The percentage of natural Tregs was decreased in extremely severe patients. The percentage of IFN-γ-producing CD8+ T cells was increased in both severe and extremely severe patients compared with mild patients. The percentage of IFN-γ-producing CD4+ T cells was increased in extremely severe patients. IL-2R, IL-6, and IL-10 were all increased in extremely severe patients. The activation of DC and B cells was decreased in extremely severe patients.CONCLUSIONThe number and function of T cells are inconsistent in COVID-19 patients. The hyperfunction of CD4+ and CD8+ T cells is associated with the pathogenesis of extremely severe SARS-CoV-2 infection.FUNDINGThis work was funded by the National Mega Project on Major Infectious Disease Prevention (2017ZX10103005-007) and the Fundamental Research Funds for the Central Universities (2019kfyRCPY098).

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.

BACKGROUND: An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. METHODS: In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. FINDINGS: Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3-11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. INTERPRETATION: The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1-2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. FUNDING: None.