Newly-Diagnosed Diabetes and Sustained Hyperglycemia are Associated with Poorer Outcomes in COVID-19 Inpatients Without Pre-Existing Diabetes.

PURPOSE: To analyze the impact of hyperglycemia on the clinical outcome of COVID-19 in patients with newly diagnosed diabetes (NDD). PATIENTS AND METHODS: We performed a retrospective study of 3114 cases of COVID-19 without pre-existing diabetes, 351 of which had NDD, in Hubei Province, China. The Cox regression model was used to calculate the risk of adverse clinical outcomes comparing the NDD vs non-NDD group before and after propensity score-matched (PSM) analysis. Patients with NDD were further divided into a sustained hyperglycemia group, a fluctuating group, and a remitted group based on their blood glucose levels during hospitalization as well as into hypoglycemic agent users and nonusers. RESULTS: Compared to the non-NDD individuals, individuals with NDD had a significantly increased risk of all-cause mortality (adjusted HR after PSM, 2.65; 95% CI, 1.49-4.72; P = 0.001) and secondary outcomes involving organ damage during the 28-day follow-up period. Subgroup analyses indicated that among individuals with NDD, the individuals with remitted hyperglycemia had the lowest 28-day mortality, whereas those with sustained hyperglycemia had the highest (IRR 24.27; 95% CI, 3.21-183.36; P < 0.001). Moreover, individuals treated with hypoglycemic agents had significantly lower all-cause mortality than those not treated with hypoglycemic agents (IRR 0.08; 95% CI, 0.01-0.56; P < 0.001). CONCLUSION: Our study reinforces the clinical message that NDD is strongly associated with poor outcomes in COVID-19 patients. Furthermore, resolved hyperglycemia in the later phase of the disease and the use of hypoglycemic agents were associated with improved prognosis in patients with NDD.

Risk factors for COVID-19 progression and mortality in hospitalized patients without pre-existing comorbidities.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic continues to escalate intensively worldwide. Massive studies on general populations with SARS-CoV-2 infection have revealed that pre-existing comorbidities were a major risk factor for the poor prognosis of COVID-19. Notably, 49-75% of COVID-19 patients had no comorbidities, but this cohort would also progress to severe COVID-19 or even death. However, risk factors contributing to disease progression and death in patients without chronic comorbidities are largely unknown; thus, specific clinical interventions for those patients are challenging. METHODS: A multicenter, retrospective study based on 4806 COVID-19 patients without chronic comorbidities was performed to identify potential risk factors contributing to COVID-19 progression and death using LASSO and a stepwise logistic regression model. RESULTS: Among 4806 patients without pre-existing comorbidities, the proportions with severe progression and mortality were 34.29% and 2.10%, respectively. The median age was 47.00 years [interquartile range, 36.00-56.00], and 2162 (44.99%) were men. Among 51 clinical parameters on admission, age ≥ 47, oxygen saturation < 95%, increased lactate dehydrogenase, neutrophil count, direct bilirubin, creatine phosphokinase, blood urea nitrogen levels, dyspnea, increased blood glucose and prothrombin time levels were associated with COVID-19 mortality in the entire cohort. Of the 3647 patients diagnosed with non-severe COVID-19 on admission, 489(13.41%) progressed to severe disease. The risk factors associated with COVID-19 progression from non-severe to severe illness were increased procalcitonin levels, SpO2 < 95%, age ≥ 47, increased LDH, activated partial thromboplastin time levels, decreased high-density lipoprotein cholesterol levels, dyspnea and increased D-dimer levels. CONCLUSIONS: COVID-19 patients without pre-existing chronic comorbidities have specific traits and disease patterns. COVID-19 accompanied by severe bacterial infections, as indicated by increased procalcitonin levels, was highly associated with disease progression from non-severe to severe. Aging, impaired respiratory function, coagulation dysfunction, tissue injury, and lipid metabolism dysregulation were also associated with disease progression. Once factors for multi-organ damage were elevated and glucose increased at admission, these findings indicated a higher risk for mortality. This study provides information that helps to predict COVID-19 prognosis specifically in patients without chronic comorbidities.

Prevalence of mental health problems in frontline healthcare workers after the first outbreak of COVID-19 in China: a cross-sectional study.

BACKGROUND: More than 210,000 medical workers have fought against the outbreak of Coronavirus Disease 2019 (COVID-19) in Hubei in China since December 2019. However, the prevalence of mental health problems in frontline medical staff after fighting COVID-19 is still unknown. METHODS: Medical workers in Wuhan and other cities in Hubei Province were invited to participate a cross-sectional and convenience sampling online survey, which assessed the prevalence of anxiety, insomnia, depression, and post-traumatic stress disorder (PTSD). RESULTS: A total of 1,091 responses (33% male and 67% female) were valid for statistical analysis. The prevalence was anxiety 53%, insomnia 79%, depression 56%, and PTSD 11%. Healthcare workers in Wuhan were more likely to face risks of anxiety (56% vs. 52%, P = 0.03) and PTSD (15% vs. 9%, P = 0.03) than those in other cities of Hubei. In terms of educational attainment, those with doctoral and masters' (D/M) degrees may experience more anxiety (median of 7.0, [interquartile range (IQR) 2.0-8.5] vs. median 5.0 [IQR 5.0-8.0], P = 0.02) and PTSD (median 26.0 [IQR 19.5-33.0] vs. median 23.0 [IQR 19.0-31.0], P = 0.04) than those with lower educational degrees. CONCLUSIONS: The mental problems were an important issue for the healthcare workers after COVID-19. Thus, an early intervention on such mental problems is necessary for healthcare workers.

Extracorporeal Membrane Oxygenation Therapy for Critically Ill Coronavirus Disease 2019 Patients in Wuhan, China: A Retrospective Multicenter Cohort Study.

Currently, little in-depth evidence is known about the application of extracorporeal membrane oxygenation (ECMO) therapy in coronavirus disease 2019 (COVID-19) patients. This retrospective multicenter cohort study included patients with COVID-19 at 7 designated hospitals in Wuhan, China. The patients were followed up until June 30, 2020. Univariate and multivariate logistic regression analyses were performed to identify the risk factors associated with unsuccessful ECMO weaning. Propensity score matching was used to match patients who received veno-venous ECMO with those who received invasive mechanical ventilation (IMV)-only therapy. Of 88 patients receiving ECMO therapy, 27 and 61 patients were and were not successfully weaned from ECMO, respectively. Additionally, 15, 15, and 65 patients were further weaned from IMV, discharged from hospital, or died during hospitalization, respectively. In the multivariate logistic regression analysis, a lymphocyte count ≤0.5×109/L and D-dimer concentration >4× the upper limit of normal level at ICU admission, a peak PaCO2 >60 mmHg at 24 h before ECMO initiation, and no tracheotomy performed during the ICU stay were independently associated with lower odds of ECMO weaning. In the propensity score-matched analysis, a mixed-effect Cox model detected a lower hazard ratio for 120-day all-cause mortality after ICU admission during hospitalization in the ECMO group. The presence of lymphocytopenia, higher D-dimer concentrations at ICU admission and hypercapnia before ECMO initiation could help to identify patients with a poor prognosis. Tracheotomy could facilitate weaning from ECMO. ECMO relative to IMV-only therapy was associated with improved outcomes in critically ill COVID-19 patients.

The Neutrophil-to-Lymphocyte Ratio Determines Clinical Efficacy of Corticosteroid Therapy in Patients with COVID-19.

Corticosteroid therapy is now recommended as a treatment in patients with severe COVID-19. But one key question is how to objectively identify severely ill patients who may benefit from such therapy. Here, we assigned 12,862 COVID-19 cases from 21 hospitals in Hubei Province equally to a training and a validation cohort. We found that a neutrophil-to-lymphocyte ratio (NLR) > 6.11 at admission discriminated a higher risk for mortality. Importantly, however, corticosteroid treatment in such individuals was associated with a lower risk of 60-day all-cause mortality. Conversely, in individuals with an NLR ≤ 6.11 or with type 2 diabetes, corticosteroid treatment was not associated with reduced mortality, but rather increased risks of hyperglycemia and infections. These results show that in the studied cohort corticosteroid treatment is associated with beneficial outcomes in a subset of COVID-19 patients who are non-diabetic and with severe symptoms as defined by NLR.

Development and validation of a risk score using complete blood count to predict in-hospital mortality in COVID-19 patients.

BACKGROUND: To develop a sensitive risk score predicting the risk of mortality in patients with coronavirus disease 2019 (COVID-19) using complete blood count (CBC). METHODS: We performed a retrospective cohort study from a total of 13,138 inpatients with COVID-19 in Hubei, China, and Milan, Italy. Among them, 9,810 patients with ≥2 CBC records from Hubei were assigned to the training cohort. CBC parameters were analyzed as potential predictors for all-cause mortality and were selected by the generalized linear mixed model (GLMM). FINDINGS: Five risk factors were derived to construct a composite score (PAWNN score) using the Cox regression model, including platelet counts, age, white blood cell counts, neutrophil counts, and neutrophil:lymphocyte ratio. The PAWNN score showed good accuracy for predicting mortality in 10-fold cross-validation (AUROCs 0.92-0.93) and subsets with different quartile intervals of follow-up and preexisting diseases. The performance of the score was further validated in 2,949 patients with only 1 CBC record from the Hubei cohort (AUROC 0.97) and 227 patients from the Italian cohort (AUROC 0.80). The latent Markov model (LMM) demonstrated that the PAWNN score has good prediction power for transition probabilities between different latent conditions. CONCLUSIONS: The PAWNN score is a simple and accurate risk assessment tool that can predict the mortality for COVID-19 patients during their entire hospitalization. This tool can assist clinicians in prioritizing medical treatment of COVID-19 patients. FUNDING: This work was supported by National Key R&D Program of China (2016YFF0101504, 2016YFF0101505, 2020YFC2004702, 2020YFC0845500), the Key R&D Program of Guangdong Province (2020B1111330003), and the medical flight plan of Wuhan University (TFJH2018006).

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19.

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19.

BACKGROUND: Dipeptidyl peptidase-4 (DPP4) is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects. Recent structural analyses indicated a potential tight interaction between DPP4 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raising a promising hypothesis that DPP4 inhibitor (DPP4i) drugs might be an optimal strategy for treating coronavirus disease 2019 (COVID-19) among patients with diabetes. However, there has been no direct clinical evidence illuminating the associations between DPP4i use and COVID-19 outcomes. AIM: To illuminate the associations between DPP4i usage and the adverse outcomes of COVID-19. METHODS: We conducted a multicenter, retrospective analysis including 2563 patients with type 2 diabetes who were hospitalized due to COVID-19 at 16 hospitals in Hubei Province, China. After excluding ineligible individuals, 142 patients who received DPP4i drugs and 1115 patients who received non-DPP4i oral anti-diabetic drugs were included in the subsequent analysis. We performed a strict propensity score matching (PSM) analysis where age, sex, comorbidities, number of oral hypoglycemic agents, heart rate, blood pressure, pulse oxygen saturation (SpO2) < 95%, CT diagnosed bilateral lung lesions, laboratory indicators, and proportion of insulin usage were matched. Finally, 111 participants treated with DPP4i drugs were successfully matched to 333 non-DPP4i users. Then, a linear logistic model and mixed-effect Cox model were applied to analyze the associations between in-hospital DPP4i use and adverse outcomes of COVID-19. RESULTS: After rigorous matching and further adjustments for imbalanced variables in the linear logistic model and Cox adjusted model, we found that there was no significant association between in-hospital DPP4i use (DPP4i group) and 28-d all-cause mortality (adjusted hazard ratio = 0.44, 95%CI: 0.09-2.11, P = 0.31). Likewise, the incidences and risks of secondary outcomes, including septic shock, acute respiratory distress syndrome, or acute organ (kidney, liver, and cardiac) injuries, were also comparable between the DPP4i and non-DPP4i groups. The performance of DPP4i agents in achieving glucose control (e.g., the median level of fasting blood glucose and random blood glucose) and inflammatory regulation was approximately equivalent in the DPP4i and non-DPP4i groups. Furthermore, we did not observe substantial side effects such as uncontrolled glycemia or acidosis due to DPP4i application relative to the use of non-DPP4i agents in the study cohort. CONCLUSION: Our findings demonstrated that DPP4i use is not significantly associated with poor outcomes of COVID-19 or other adverse effects of anti-diabetic treatment. The data support the continuation of DPP4i agents for diabetes management in the setting of COVID-19.

Kidney Function Indicators Predict Adverse Outcomes of COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is a recently emerged respiratory infectious disease with kidney injury as a part of the clinical complications. However, the dynamic change of kidney function and its association with COVID-19 prognosis are largely unknown. METHODS: In this multicenter retrospective cohort study, we analyzed clinical characteristics, medical history, laboratory tests, and treatment data of 12,413 COVID-19 patients. The patient cohort was stratified according to the severity of the outcome into three groups: non-severe, severe, and death. FINDINGS: The prevalence of elevated blood urea nitrogen (BUN), elevated serum creatinine (Scr), and decreased blood uric acid (BUA) at admission was 6.29%, 5.22%, and 11.66%, respectively. The trajectories showed the elevation in BUN and Scr levels, as well as a reduction in BUA level for 28 days after admission in death cases. Increased all-cause mortality risk was associated with elevated baseline levels of BUN and Scr and decreased levels of BUA. CONCLUSIONS: The dynamic changes of the three kidney function markers were associated with different severity and poor prognosis of COVID-19 patients. BUN showed a close association with and high potential for predicting adverse outcomes in COVID-19 patients for severity stratification and triage. FUNDING: This study was supported by grants from the National Key R&D Program of China (2016YFF0101504), the National Science Foundation of China (81630011, 81970364, 81970070, 81970011, 81870171, and 81700356), the Major Research Plan of the National Natural Science Foundation of China (91639304), the Hubei Science and Technology Support Project (2019BFC582, 2018BEC473, and 2017BEC001), and the Medical Flight Plan of Wuhan University.

Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes.

The safety and efficacy of anti-diabetic drugs are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type 2 diabetes (T2D). Metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified. Our current retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID-19, but not with 28-day COVID-19-related mortality. Furthermore, metformin use was significantly associated with reduced heart failure and inflammation. Our findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.

Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.

Longitudinal Association Between Markers of Liver Injury and Mortality in COVID-19 in China.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is a new infectious disease. To reveal the hepatic injury related to this disease and its clinical significance, we conducted a multicenter retrospective cohort study that included 5,771 adult patients with COVID-19 pneumonia in Hubei Province. APPROACH AND RESULTS: We reported the distributional and temporal patterns of liver injury indicators in these patients and determined their associated factors and death risk. Longitudinal liver function tests were retrospectively analyzed and correlated with the risk factors and death. Liver injury dynamic patterns differed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL). AST elevated first, followed by ALT, in severe patients. ALP modestly increased during hospitalization and largely remained in the normal range. The fluctuation in TBIL levels was mild in the non-severe and the severe groups. AST abnormality was associated with the highest mortality risk compared with the other indicators of liver injury during hospitalization. Common factors associated with elevated liver injury indicators were lymphocyte count decrease, neutrophil count increase, and male gender. CONCLUSION: The dynamic patterns of liver injury indicators and their potential risk factors may provide an important explanation for the COVID-19-associated liver injury. Because elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk, our study indicates that these parameters should be monitored during hospitalization.

Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes.

Type 2 diabetes (T2D) is a major comorbidity of COVID-19. However, the impact of blood glucose (BG) control on the degree of required medical interventions and on mortality in patients with COVID-19 and T2D remains uncertain. Thus, we performed a retrospective, multi-centered study of 7,337 cases of COVID-19 in Hubei Province, China, among which 952 had pre-existing T2D. We found that subjects with T2D required more medical interventions and had a significantly higher mortality (7.8% versus 2.7%; adjusted hazard ratio [HR], 1.49) and multiple organ injury than the non-diabetic individuals. Further, we found that well-controlled BG (glycemic variability within 3.9 to 10.0 mmol/L) was associated with markedly lower mortality compared to individuals with poorly controlled BG (upper limit of glycemic variability exceeding 10.0 mmol/L) (adjusted HR, 0.14) during hospitalization. These findings provide clinical evidence correlating improved glycemic control with better outcomes in patients with COVID-19 and pre-existing T2D.

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19.

RATIONALE: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. OBJECTIVE: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. METHODS AND RESULTS: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55-68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57-69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19-0.92]; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15-0.89]; P=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12-0.70]; P=0.01) in patients with COVID-19 and coexisting hypertension. CONCLUSIONS: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.