Treatment of Coronavirus Disease 2019 Patients With Prolonged Postsymptomatic Viral Shedding With Leflunomide: A Single-center Randomized Controlled Clinical Trial.

BACKGROUND: We aimed to evaluate the efficacy and safety of leflunomide, an approved dihydroorotate dehydrogenase inhibitor, to treat coronavirus disease 2019 (COVID-19) patients with prolonged postsymptomatic viral shedding. METHODS: We conducted a prospective, randomized controlled, open-label trial involving hospitalized adult COVID-19 patients with prolonged polymerase chain reaction (PCR) positivity. Patients were randomly assigned to receive either leflunomide (50 mg every 12 hours, 3 consecutive times, orally; then 20 mg once daily for 8 days), in addition to nebulized interferon alpha 2a (IFN-α-2a, 3 million IU each time, twice daily for 10 days), or nebulized IFN-α-2a alone for 10 days. The primary endpoint was the duration of viral shedding. RESULTS: A total of 50 COVID-19 patients with prolonged PCR positivity were randomized into 2 groups: 26 were assigned to the leflunomide plus IFN-α-2a group, and 24 were assigned to the interferon-alone group. Treatment with leflunomide was not associated with a difference from the interferon-alone group in the duration of viral shedding (hazard ratio for negative reverse-transcription PCR, 0.70 [95% confidence interval, .391-1.256]; P = .186). In addition, the patients given leflunomide did not have a substantially shorter length of hospital stay than patients treated with interferon alone, with median durations of 29.0 (interquartile range [IQR], 19.3-47.3) days and 33.0 (IQR, 29.3-42.8) days, respectively (P = .170). Two leflunomide recipients were unable to complete the full 10-day course of administration due to adverse events. CONCLUSIONS: In COVID-19 patients with prolonged PCR positivity, no benefit in terms of the duration of viral shedding was observed with the combined treatment of leflunomide and IFN-α-2a beyond IFN-α-2a alone.

Diagnostic value of using a combination of nucleic acid and specific antibody tests for SARS-CoV-2 in coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) is a newly emerged disease with various clinical manifestations and imaging features. The diagnosis of COVID-19 depends on a positive nucleic acid amplification test by real-time reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the clinical manifestations and imaging features of COVID-19 are non-specific, and nucleic acid test for SARS-CoV-2 can have false-negative results. It is presently believed that detection of specific antibodies to SARS-CoV-2 is an effective screening and diagnostic indicator for SARS-CoV-2 infection. Thus, a combination of nucleic acid and specific antibody tests for SARS-CoV-2 will be more effective to diagnose COVID-19, especially to exclude suspected cases.

Abnormal immunity of non-survivors with COVID-19: predictors for mortality.

BACKGROUND: The number of coronavirus disease 2019 (COVID-19) cases has rapidly increased all over the world. Specific information about immunity in non-survivors with COVID-19 is scarce. This study aimed to analyse the clinical characteristics and abnormal immunity of the confirmed COVID-19 non-survivors. METHODS: In this single-centered, retrospective, observational study, we enrolled 125 patients with COVID-19 who were died between January 13 and March 4, 2020 in Renmin Hospital of Wuhan University. A total of 414 randomly recruited patients with confirmed COVID-19 who were discharged from the same hospital during the same period served as control. The demographic, clinical characteristics and laboratory findings at admission, and treatment used in these patients were collected. The immunity-related risk factors associated with in-hospital death were tested by logistic regression models and Receiver Operating Characteristic (ROC) curve. RESULTS: Non-survivors (70 years, IQR: 61.5-80) were significantly older than survivors (54 years, IQR: 37-65) (P <  0.001). 56.8% of non-survivors was male. Nearly half of the patients (44.9%) had chronic medical illness. In non-survivors, hypertension (49.6%) was the most common comorbidity, followed by diabetes (20.0%) and coronary heart disease (16.0%). The common signs and symptoms at admission of non-survivors were fever (88%), followed by cough (64.8%), dyspnea (62.4%), fatigue (62.4%) and chest tightness (58.4%). Compared with survivors, non-survivors had higher white blood cell (WBC) count (7.85 vs 5.07 × 109/L), more elevated neutrophil count (6.41 vs 3.08 × 109/L), smaller lymphocyte count (0.69 vs 1.20 × 109/L) and lower platelet count (172 vs 211 × 109/L), raised concentrations of procalcitonin (0.21 vs 0.06 ng/mL) and CRP (70.5 vs 7.2 mg/L) (P < 0.001). This was accompanied with significantly decreased levels of CD3+ T cells (277 vs 814 cells/µl), CD4+ T cells (172 vs 473 cells/µl), CD8+ T cells (84 vs 262.5 cells/µl, P < 0.001), CD19+ T cells (88 vs 141 cells/µl) and CD16+ 56+ T cells (79 vs 128.5 cells/µl) (P < 0.001). The concentrations of immunoglobulins (Ig) G (13.30 vs 11.95 g/L), IgA (2.54 vs 2.21 g/L), and IgE (71.30 vs 42.25 IU/ml) were increased, whereas the levels of complement proteins (C)3 (0.89 vs 0.99 g/L) and C4 (0.22 vs 0.24 g/L) were decreased in non-survivors when compared with survivors (all P < 0.05). The non-survivors presented lower levels of oximetry saturation (90 vs 97%) at rest and lactate (2.40 vs 1.90 mmol/L) (P < 0.001). Old age, comorbidity of malignant tumor, neutrophilia, lymphocytopenia, low CD4+ T cells, decreased C3, and low oximetry saturation were the risk factors of death in patients with confirmed COVID-19. The frequency of CD4+ T cells positively correlated with the numbers of lymphocytes (r = 0.787) and the level of oximetry saturation (r = 0.295), Whereas CD4+ T cells were negatively correlated with age (r =-0.323) and the numbers of neutrophils (r = - 0.244) (all P < 0.001). CONCLUSIONS: Abnormal cellular immunity and humoral immunity were key features of non-survivors with COVID-19. Neutrophilia, lymphocytopenia, low CD4+ T cells, and decreased C3 were immunity-related risk factors predicting mortality of patients with COVID-19.

Asymptomatic infection by SARS-CoV-2 in healthcare workers: A study in a large teaching hospital in Wuhan, China.

OBJECTIVES: To investigate the proportion and characteristics of asymptomatic infection among healthcare workers (HCWs). METHODS: This study retrospectively investigated 1407 HCWs who were screened for COVID-19 by chest computed tomography (CT) scans and nasopharyngeal swabs for SARS-CoV-2 nucleic acid. Demographics, CT features, nasopharyngeal swabs, baseline symptoms, and laboratory data were collected. RESULTS: Of 1407 HCWs, 235 had symptoms and 1172 were asymptomatic close contacts, of which, 107 were symptomatic cases and 84 were close contacts who had abnormal CT findings. Of 152 symptomatic individuals and 908 close contacts tested for SARS-CoV-2 nucleic acid, 122 symptomatic cases and 38 close contacts had positive reverse-transcriptase real-time polymerase chain (RT-PCR) test results. The rate of confirmed asymptomatic infections was 4.2% (38/908). Both symptomatic and asymptomatic infected cases had high titrations of specific IgG or had ≥four-fold increase in IgG during convalescence compared with the acute phase. Combining the RT-PCR tests and serological findings, the rate of asymptomatic infections was 9.7% (88/908). In terms of the duration of viral shedding, there was no significant difference between symptomatic mild/moderate participants and asymptomatic infections. CONCLUSIONS: The findings demonstrated that a high rate of asymptomatic SARS-CoV-2 carriers existed among healthcare worker close contacts during the outbreak of COVID-19.

A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial.

We recently reported that inhibitors against human dihydroorotate dehydrogenase (DHODH) have broad-spectrum antiviral activities including their inhibitory efficacies on SARS-CoV-2 replication in infected cells. However, there are limited data from clinical studies to prove the application of DHODH inhibitors in Coronavirus disease 2019 (COVID-19) patients. In the present study, we evaluated Leflunomide, an approved DHODH inhibitor widely used as a modest immune regulator to treat autoimmune diseases, in treating COVID-19 disease with a small-scale of patients. Cases of 10 laboratory-confirmed COVID-19 patients of moderate type with obvious opacity in the lung were included. Five of the patients were treated with Leflunomide, and another five were treated as blank controls without a placebo. All the patients accepted standard supportive treatment for COVID-19. The patients given Leflunomide had a shorter viral shedding time (median of 5 days) than the controls (median of 11 days, P = 0.046). The patients given Leflunomide also showed a significant reduction in C-reactive protein levels, indicating that immunopathological inflammation was well controlled. No obvious adverse effects were observed in Leflunomide-treated patients, and they all discharged from the hospital faster than controls. This preliminary study on a small-scale compassionate use of Leflunomide provides clues for further understanding of Leflunomide as a potential antiviral drug against COVID-19.

Clinical features in 52 patients with COVID-19 who have increased leukocyte count: a retrospective analysis.

Recent reports have showed that a proportion of patients with Coronavirus Disease 2019 (COVID-19) presented elevated leukocyte count. Clinical data about these patients is scarce. We aimed to evaluate the clinical findings of patients with COVID-19 who have increased leukocyte at admission. We retrospectively collected the clinical data on the 52 patients who have increased leukocyte count at admission from the 619 patients with confirmed COVID-19 who had pneumonia with abnormal features on chest CT scan in Renmin Hospital of Wuhan University in Wuhan, China, from February 3 to March 3, 2020. The mean age of the 52 patients with increased leukocyte count was 64.7 (SD 11.4) years, 32 (61.5%) were men and 47 (90.4%) had fever. Compared with the patients with non-increased leukocyte count, the patients with increased leukocyte count were significantly older (P < 0.01), were more likely to have underlying chronic diseases (P < 0.01), more likely to develop critically illness (P < 0.01), more likely to admit to an ICU (P < 0.01), more likely to receive mechanical ventilation (P < 0.01), had higher rate of death (P < 0.01) and the blood levels of neutrophil count and the serum concentrations of CRP and IL-6 were significantly increased, (P < 0.01). The older patients with COVID-19 who had underlying chronic disorders are more likely to develop leukocytosis. These patients are more likely to develop critical illness, with a high admission to an ICU and a high mortality rate.

Abnormal immunity of non-survivors with COVID-19: predictors for mortality (preprint)

Background The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread all over the world. The specific information about immunity of non-survivors with COVID-19 is scarce. We aimed to describe the clinical characteristics and abnormal immunity of the confirmed COVID-19 non-survivors.Methods In this single-centered, retrospective, observational study, we enrolled 125 patients with COVID-19 who were died between Jan, 13 and Mar 4, 2020 from Renmin Hospital of Wuhan University. 414 randomly recruited patients with confirmed COVID-19 who were discharged from the same hospital during the same period served as control. Demographic and clinical characteristics, laboratory findings and chest computed tomograph results at admission, and treatment were collected. The immunity-related risk factors associated with in-hospital death were detected.Results Non-survivors were older than survivors. More than half of non-survivors was male. Nearly half of the patients had chronic medical illness. The common signs and symptoms at admission of non-survivors were fever. Non-survivors had higher white blood cell (WBC) count, more elevated neutrophil count, lower lymphocytes and platelete count, raised concentration of procalcitonin and C-reactive protein (CRP) than survivors. The levels of CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ T cells, and CD16+56+T cells were significantly decreased in non-survivors when compared with survivors. The concentrations of immunoglobulins (Ig) G, IgA and IgE were increased, whereas the levels of complement proteins (C)3 and C4 were decreased in non-survivors when compared with survivors. Non-survivors presented lower levels of oximetry saturation at rest and lactate. Old age, comorbidity of malignant tumour, neutrophilia, lymphocytopenia, low CD4+ T cells, decreased C3, and low oximetry saturation were the risk factors of death in patients with confirmed COVID-19. The frequency of CD4+ T cells positively correlated with the numbers of lymphocytes and the level of oximetry saturation, whereas CD4+ T cells were negatively correlated with age and the numbers of neutrophils.Conclusion Abnormal cellular immunity and humoral immunity were considerable in non-survivors with COVID-19. Neutrophilia, lymphocytopenia, low CD4+ T cells, and decreased C3 were the immunity-related risk factors predicting mortality of patients with COVID-19.

A preliminary evaluation on the efficacy of ozone therapy in the treatment of COVID-19

Currently, coronavirus disease 2019 (COVID-19) is a global pandemic disease with significant morbidity and mortality. Ozone may exert its antiviral actions and ozone therapy has been demonstrated therapeutically usefulness in influenza and novel viruses. In this letter, two severe cases with COVID-19 received ozone therapy were described. The results showed that ozone therapy may promote recovery of clinical condition and improvement of chest CT images, shorten the duration of viral shedding and length of hospital stay. This article is protected by copyright. All rights reserved.