Redox imbalance in COVID-19 pathophysiology

Background The pathophysiologic significance of redox imbalance is unquestionable as numerous reports and topic reviews indicate alterations in redox parameters during corona virus disease 2019 (COVID-19). However, a more comprehensive understanding of redox-related parameters in the context of COVID-19-mediated inflammation and pathophysiology is required. Methods COVID-19 subjects (n = 64) and control subjects (n = 19) were enrolled, and blood was drawn within 72 hours of diagnosis. Serum multiplex assay and buffy coat cell mRNA sequencing was performed. Oxidant/free radical (electron paramagnetic resonance (EPR) spectroscopy, nitrite-nitrate assay) and antioxidant (ferrous reducing ability of serum assay and high-performance liquid chromatography) were performed. Multivariate analyses were performed to evaluate potential of indicated parameters to predict clinical outcome. Results Significantly greater levels of multiple inflammatory and vascular markers were quantified in the subjects admitted to the ICU compared to non-ICU subjects. Gene set enrichment analyses indicated significant enhancement of oxidant related pathways and biochemical assays confirmed a significant increase in free radical production and uric acid reduction in COVID-19 subjects. Multivariate analyses confirmed a positive association between serum levels of VCAM-1, ICAM-1 and a negative association between the abundance of one electron oxidants (detected by ascorbate radical formation) and mortality in COVID subjects while IL-17c and TSLP levels predicted need for intensive care in COVID-19 subjects. Conclusion Herein we demonstrate a significant redox imbalance during COVID-19 infection affirming the potential for manipulation of oxidative stress pathways as a new therapeutic strategy COVID-19. However, further work is requisite for detailed identification of oxidants (O2•-, H2O2 and/or circulating transition metals such as Fe or Cu) contributing to this imbalance to avoid the repetition of failures using non-specific antioxidant supplementation. Graphical Image 1

Clinical Characteristics of Recurrent-positive Coronavirus Disease 2019 after Curative Discharge: a retrospective analysis of 15 cases in Wuhan China (preprint)

In China, the patients with previously negative RT-PCR results again test positive during the post-discharge isolation period. We aimed to determine the clinical characteristics of these recurrent-positive patients. We retrospectively reviewed the data of 15 recurrent-positive patients and 107 control patients with non-recurrent, moderate COVID-19 treated in Wuhan, China. Clinical data and laboratory results were comparatively analyzed. We found that recurrent-positive patients had moderate disease. The rate of recurrent-positive disease in our hospital was 1.87%. Recurrent-positive patients were significantly younger (43(35-54) years) than control patients (60(43-69) years) (P=0.011). The early LOS (length of stay in hospital before recurrence) was significantly longer in recurrent-positive patients (36(34-45) days) than in control patients (15(7-30) days) (P =0.001). The time required for the first conversion of RT-PCR results from positive to negative was significantly longer in recurrent-positive patients (14(10-17) days) than in control patients (6(3-9) days) (P =0.011). Serum COVID-19 antibody levels were significantly lower in recurrent-positive patients than in control patients (IgM: 13.69 {+/-} 4.38 vs. 68.10 {+/-} 20.85 AU/mL, P = 0.015; IgG: 78.53 {+/-} 9.30 vs. 147.85 {+/-} 13.33 AU/mL, P < 0.0001). Recurrent-positive patients were younger than control patients. The early LOS (length of stay in hospital before recurrence) was significantly longer in recurrent-positive group than that in control group. COVID-19 IgM/IgG antibody levels were significantly lower in recurrent-positive group than those in control group, which might explain why the virus RNA RT-PCR was positive after the initial clinical cure(with three times of virus RNA RT-PCR negative). The virus might not be fully eliminated because of the lower IgG level and their later replicating might result in recurrent-positive virus RNA RT-PCR.

Prognostic value of neutrophil-to-lymphocyte ratio, lactate dehydrogenase, D-dimer and CT score in patients with COVID-19 (preprint)

Background To explore the significance of neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), D-dimer and CT score in evaluating the severity and prognosis of coronavirus disease – 2019 (COVID-19).Methods Patients with laboratory confirmed COVID-19 were retrospectively enrolled. The baseline data, laboratory findings, chest computed tomography (CT) results evaluating by CT score on admission, and clinical outcomes were collected and compared. The logistic regression was used to assess the independent relationship between the baseline level of four indicators (NLR, LDH, D-dimer, CT score) and the severity of COVID-19.Results Among 432 patients, 125 (28.94%) cases were divided into severe group, the remaining (n = 307, 71.06%) were in non-severe group. In multivariate logistic regression, high level of NLR, LDH were independent predictor of the severe group in COVID-19 (OR = 2.163; 95%CI = 1.162–4.026; p = 0.015 for NLR > 3.82; OR = 2.298; 95%CI = 1.327–3.979; p = 0.003 for LDH > 246U/L). Combining NLR > 3.82 and LDH > 246U/L increased the sensitivity of diagnosis in severe patients (NLR > 3.82 [50.40%] vs. Combined diagnosis [72.80%]; p = 0.0007; LDH > 246 [59.2%] vs. Combined diagnosis [72.80%]; p < 0.0001).Conclusions High levels of NLR and LDH in serum have potential value in the early identification of severe patients with COVID-19. The combination of LDH and NLR can improve the sensitivity of diagnosis.

Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study (preprint)

The outbreak of novel coronavirus disease 2019 (COVID-19) has become a pandemic. Drug repurposing may represent a rapid way to fill the urgent need for effective treatment. We evaluated the clinical utility of chloroquine and hydroxychloroquine in treating COVID-19. Forty-eight patients with moderate COVID-19 were randomized to oral treatment with chloroquine (1000 mg QD on Day 1, then 500 mg QD for 9 days; n=18), hydroxychloroquine (200 mg BID for 10 days; n=18), or control treatment (n=12). Adverse events were mild, except for one case of Grade 2 ALT elevation. Adverse events were more commonly observed in the chloroquine group (44.44%) and the hydroxychloroquine group (50.00%) than in the control group (16.67%). The chloroquine group achieved shorter time to clinical recovery (TTCR) than the control group (P=0.019). There was a trend toward reduced TTCR in the hydroxychloroquine group (P=0.049). The time to reach viral RNA negativity was significantly faster in the chloroquine group and the hydroxychloroquine group than in the control group (P=0.006 and P=0.010, respectively). The median numbers of days to reach RNA negativity in the chloroquine, hydroxychloroquine, and control groups was 2.5 (IQR: 2.0-3.8) days, 2.0 (IQR: 2.0-3.5) days, and 7.0 (IQR: 3.0-10.0) days, respectively. The chloroquine and hydroxychloroquine groups also showed trends toward improvement in the duration of hospitalization and findings on lung computerized tomography (CT). This study provides evidence that (hydroxy)chloroquine may be used effectively in treating moderate COVID-19 and supports larger trials.