Plasma Metabolomic Profiling of Patients Recovered From Coronavirus Disease 2019 (COVID-19) With Pulmonary Sequelae 3 Months After Discharge.

BACKGROUND: Elucidation of the molecular mechanisms involved in the pathogenesis of coronavirus disease 2019 (COVID-19) may help to discover therapeutic targets. METHODS: To determine the metabolomic profile of circulating plasma from COVID-19 survivors with pulmonary sequelae 3 months after discharge, a random, outcome-stratified case-control sample was analyzed. We enrolled 103 recovered COVID-19 patients as well as 27 healthy donors, and performed pulmonary function tests, computerized tomography (CT) scans, laboratory examinations, and liquid chromatography-mass spectrometry. RESULTS: Plasma metabolite profiles of COVID-19 survivors with abnormal pulmonary function were different from those of healthy donors or subjects with normal pulmonary function. These alterations were associated with disease severity and mainly involved amino acid and glycerophospholipid metabolic pathways. Furthermore, increased levels of triacylglycerols, phosphatidylcholines, prostaglandin E2, arginine, and decreased levels of betain and adenosine were associated with pulmonary CO diffusing capacity and total lung capacity. The global plasma metabolomic profile differed between subjects with abnormal and normal pulmonary function. CONCLUSIONS: Further metabolite-based analysis may help to identify the mechanisms underlying pulmonary dysfunction in COVID-19 survivors, and provide potential therapeutic targets in the future.

Inflammatory Profiles and Clinical Features of Coronavirus 2019 Survivors 3 Months After Discharge in Wuhan, China.

BACKGROUND: Postdischarge immunity and its correlation with clinical features among patients recovered from coronavirus disease 2019(COVID-19) are poorly described. This prospective cross-sectional study explored the inflammatory profiles and clinical recovery of patients with COVID-19 at 3 months after hospital discharge. METHODS: Patients with COVID-19 discharged from 4 hospitals in Wuhan, recovered asymptomatic patients (APs) from an isolation hotel, and uninfected healthy controls (HCs) were recruited. Viral nucleic acid and antibody detection, laboratory examination, computed tomography, pulmonary function assessment, multiplex cytokine assay, and flow cytometry were performed. RESULTS: The72 age-, sex- and body mass index-matched participants included 19 patients with severe/critical COVID-19 (SPs), 20 patients with mild/moderate COVID-19 (MPs), 16 APs, and 17 HCs. At 3 months after discharge, levels of proinflammatory cytokines and factors related to vascular injury/repair in patients recovered from COVID-19 had not returned to those of the HCs, especially among recovered SPs compared with recovered MPs and APs. These cytokines were significantly correlated with impaired pulmonary function and chest computed tomographic abnormalities. However, levels of immune cells had returned to nearly normal levels and were not significantly correlated with abnormal clinical features. CONCLUSION: Vascular injury, inflammation, and chemotaxis persisted in patients with COVID-19 and were correlated with abnormal clinical features 3 months after discharge, especially in recovered SPs.

Long-Term Effects of COVID-19 on Health Care Workers 1-Year Post-Discharge in Wuhan.

INTRODUCTION: To assess the long-term consequences of coronavirus disease (COVID-19) among health care workers (HCWs) in China (hereafter surviving HCWs). METHODS: A total of 303 surviving HCWs were included. Lung (pulmonary function test, 6-min walk test [6MWT], chest CT), physical (St. George's Respiratory Questionnaire [SGRQ], Modified Medical Research Council dyspnea scale [mMRC], and Borg scale), and psychiatric functions (Essen Trauma Inventory) were evaluated during the 1-year follow-up. RESULTS: Surviving HCWs had an abnormal diffusion capacity 1 year post-discharge. Participants with a reduced carbon monoxide diffusing capacity (DLCO) comprised 43.48%. The proportion of HCWs with a median 6MWT distance below the lower limit of the normal was 19.4%. An abnormal CT pattern was observed in 37.5% of the HCWs. The SGRQ, mMRC, and Borg scores of surviving HCWs, especially those with critical/severe disease, were significantly higher than those in the normal population. Probable post-traumatic stress disorder (PTSD) was reported in 21.9% of the surviving HCWs. Diffusion capacity impairment was associated with women. Critical/severe illness and nurses were associated with impaired physical function. CONCLUSIONS: Most surviving HCWs, especially female HCWs, still had an abnormal diffusion capacity at 1 year. The physical and psychiatric functions of surviving HCWs were significantly worse than those of the healthy population. Long-term follow-up of pulmonary, physical, and psychiatric functions for surviving HCWs is required.

Changes in glomerular filtration rate and metabolomic differences in severely ill coronavirus disease survivors 3 months after discharge.

To explore the recovery of renal function in severely ill coronavirus disease (COVID-19) survivors and determine the plasma metabolomic profile of patients with different renal outcomes 3 months after discharge, we included 89 severe COVID-19 survivors who had been discharged from Wuhan Union Hospital for 3 months. All patients had no underlying kidney disease before admission. At patient recruitment, renal function assessment, laboratory examination, chest computed tomography (CT) were performed. Liquid chromatography-mass spectrometry was used to detect metabolites in the plasma. We analyzed the longitudinally change in the estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin-c levels using the CKD-EPI equation and explored the metabolomic differences in patients with different eGFR change patterns from hospitalization to 3 months after discharge. Lung CT showed good recovery; however, the median eGFR significantly decreased at the 3-month follow-up. Among the 89 severely ill COVID-19 patients, 69 (77.5%) showed abnormal eGFR (<90 mL/min per 1.73 m2) at 3 months after discharge. Age (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.08-1.47, p = 0.003), body mass index (OR = 1.97, 95% CI = 1.20-3.22, p = 0.007), and cystatin-c level (OR = 1.22, 95% CI = 1.07-1.39, p = 0.003) at discharge were independent risk factors for post-discharge abnormal eGFR. Plasma metabolomics at the 3-months follow-up revealed that ß-pseudouridine, uridine, and 2-(dimethylamino) guanosine levels gradually increased with an abnormal degree of eGFR. Moreover, the kynurenine pathway in tryptophan metabolism, vitamin B6 metabolism, cysteine and methionine metabolism, and arginine biosynthesis were also perturbed in survivors with abnormal eGFR.

Comparison of Residual Pulmonary Abnormalities 3 Months After Discharge in Patients Who Recovered From COVID-19 of Different Severity.

Background and Objectives: To investigate whether coronavirus disease 2019 (COVID-19) survivors who had different disease severities have different levels of pulmonary sequelae at 3 months post-discharge. Methods: COVID-19 patients discharged from four hospitals 3 months previously, recovered asymptomatic patients from an isolation hotel, and uninfected healthy controls (HCs) from the community were prospectively recruited. Participants were recruited at Wuhan Union Hospital and underwent examinations, including quality-of-life evaluation (St. George Respiratory Questionnaire [SGRQ]), laboratory examination, chest computed tomography (CT) imaging, and pulmonary function tests. Results: A total of 216 participants were recruited, including 95 patients who had recovered from severe/critical COVID-19 (SPs), 51 who had recovered from mild/moderate disease (MPs), 28 who had recovered from asymptomatic disease (APs), and 42 HCs. In total, 154 out of 174 (88.5%) recovered COVID-19 patients tested positive for serum SARS-COV-2 IgG, but only 19 (10.9%) were still positive for IgM. The SGRQ scores were highest in the SPs, while APs had slightly higher SGRQ scores than those of HCs; 85.1% of SPs and 68.0% of MPs still had residual CT abnormalities, mainly ground-glass opacity (GGO) followed by strip-like fibrosis at 3 months after discharge, but the pneumonic lesions were largely absorbed in the recovered SPs or MPs relative to findings in the acute phase. Pulmonary function showed that the frequency of lung diffusion capacity for carbon monoxide abnormalities were comparable in SPs and MPs (47.1 vs. 41.7%), while abnormal total lung capacity (TLC) and residual volume (RV) were more frequent in SPs than in MPs (TLC, 18.8 vs. 8.3%; RV, 11.8 vs. 0%). Conclusions: Pulmonary abnormalities remained after recovery from COVID-19 and were more frequent and conspicuous in SPs at 3 months after discharge.

Clinical Characteristics and Outcomes of Severe or Critical COVID-19 Patients Presenting No Respiratory Symptoms or Fever at Onset.

It is difficult to identify suspected cases of atypical patients with coronavirus disease 2019 (COVID-19), and data on severe or critical patients are scanty. This retrospective study presents the clinical, laboratory, and radiological profiles, treatments, and outcomes of atypical COVID-19 patients without respiratory symptoms or fever at onset. The study examined ten atypical patients out of 909 severe or critical patients diagnosed with COVID-19 in Wuhan Union Hospital West Campus between 25 January 2020 and 10 February 2020. Data were obtained from the electronic medical records of severe or critical patients without respiratory symptoms or fever at onset. Outcomes were followed up to discharge or death. Among 943 COVID-19 patients, 909 (96.4%) were severe or critical type. Of the severe or critical patients, ten (1.1%) presented without respiratory symptoms or fever at admission. The median age of the ten participants was 63 years (interquartile range (IQR): 57-72), and seven participants were men. The median time from symptom onset to admission was 14 d (IQR: 7-20). Eight of the ten patients had chronic diseases. The patients had fatigue (n = 5), headache or dizziness (n = 4), diarrhea (n = 5), anorexia (n = 3), nausea or vomiting (n = 3), and eye discomfort (n = 1). Four patients were found to have lymphopenia. Imaging examination revealed that nine patients had bilateral pneumonia and one had unilateral pneumonia. Eventually, two patients died and eight were discharged. In the discharged patients, the median time from admission to discharge lasted 24 d (IQR: 13-43). In summary, some severe or critical COVID-19 patients were found to have no respiratory symptoms or fever at onset. All such atypical cases should be identified and quarantined as early as possible, since they tend to have a prolonged hospital stay or fatal outcomes. Chest computed tomography (CT) scan and nucleic acid detection should be performed immediately on close contacts of COVID-19 patients to screen out those with atypical infections, even if the contacts present without respiratory symptoms or fever at onset.

The Correlation Between Clinical Features and Viral RNA Shedding in Outpatients With COVID-19.

BACKGROUND: Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can shed virus, thereby causing human-to-human transmission, and the viral RNA shedding is commonly used as a proxy measure for infectivity. METHODS: We retrospectively reviewed confirmed cases of COVID-19 who attended the fever clinic of Wuhan Union Hospital from January 14 to February 24. In terms of the viral RNA shedding (median values) at first visit, patients were divided into a high-viral RNA shedding group and a low-viral RNA shedding group. Univariate and multivariate logistic regression analysis were performed to investigate the correlation between viral RNA shedding and clinical features. RESULTS: A total of 918 consecutive COVID-19 patients were enrolled, and severe patients made up 26.1%. After univariate and multivariate logistic regression, advanced age (odds ratio [OR], 1.02; 95% CI, 1.01-1.03; P = .001), having severe chronic diseases (OR, 1.44; 95% CI, 1.03-2.01; P = .04), and severe illness (OR, 1.60; 95% CI, 1.12-2.28; P = .01) were independent risk factors for high viral RNA shedding. Shorter time interval from symptom onset to viral detection was a protective factor for viral RNA shedding (OR, 0.97; 95% CI, 0.94-0.99; P = .01). Compared with mild patients, severe patients have higher virus shedding over a long period of time after symptom onset (P = .01). CONCLUSIONS: Outpatients who were old, had severe illness, and had severe underlying diseases had high viral RNA shedding.

Development and validation of a risk factor-based system to predict short-term survival in adult hospitalized patients with COVID-19: a multicenter, retrospective, cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a public health emergency of global concern. We aimed to explore the risk factors of 14-day and 28-day mortality and develop a model for predicting 14-day and 28-day survival probability among adult hospitalized patients with COVID-19. METHODS: In this multicenter, retrospective, cohort study, we examined 828 hospitalized patients with confirmed COVID-19 hospitalized in Wuhan Union Hospital and Central Hospital of Wuhan between January 12 and February 9, 2020. Among the 828 patients, 516 and 186 consecutive patients admitted in Wuhan Union Hospital were enrolled in the training cohort and the validation cohort, respectively. A total of 126 patients hospitalized in Central Hospital of Wuhan were enrolled in a second external validation cohort. Demographic, clinical, radiographic, and laboratory measures; treatment; proximate causes of death; and 14-day and 28-day mortality are described. Patients' data were collected by reviewing the medical records, and their 14-day and 28-day outcomes were followed up. RESULTS: Of the 828 patients, 146 deaths were recorded until May 18, 2020. In the training set, multivariate Cox regression indicated that older age, lactate dehydrogenase level over 360 U/L, neutrophil-to-lymphocyte ratio higher than 8.0, and direct bilirubin higher than 5.0 µmol/L were independent predictors of 28-day mortality. Nomogram scoring systems for predicting the 14-day and 28-day survival probability of patients with COVID-19 were developed and exhibited strong discrimination and calibration power in the two external validation cohorts (C-index, 0.878 and 0.839). CONCLUSION: Older age, high lactate dehydrogenase level, evaluated neutrophil-to-lymphocyte ratio, and high direct bilirubin level were independent predictors of 28-day mortality in adult hospitalized patients with confirmed COVID-19. The nomogram system based on the four factors revealed good discrimination and calibration, suggesting good clinical utility.