Gout and the COVID-19 pandemic.

PURPOSE OF REVIEW: This review gives an overview of recently published articles on COVID-19 and gout. RECENT FINDINGS: People with gout are likely to be at an increased risk of poor outcomes after COVID-19 infection due to comorbid cardiometabolic conditions. The effects of chronic hyperuricemia on trained immunity, and the hyperinflammatory state induced by gout itself may also play a role. Frequent courses of glucocorticoids for gout flares may be associated with adverse outcomes after COVID-19 infection and reduced immunogenicity to the COVID-19 vaccination. Similarities between the pathophysiology of gout flares and the dysregulated inflammatory response of severe COVID-19 have been identified. Medications used in the treatment of gout, including colchicine and interleukin-1 inhibitors, have shown promise in the treatment of COVID-19 in clinical trials. Overall, the COVID-19 pandemic has had a negative impact on gout care, with patients reporting more difficulty with disease control, accessing medications and healthcare, and poorer quality of life. SUMMARY: The COVID-19 pandemic has created many challenges for people with gout. At present, there is a lack of guidance on the management of gout during the pandemic and paucity of research assessing outcomes of COVID-19 infection in people with gout.

Hmong microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C): A phase II clinical study protocol.

BACKGROUND: Hmong men in Minnesota exhibit a high prevalence of gout and hyperuricemia. Although evidence of vitamin C's effectiveness as a treatment for gout is mixed, analysis of therapeutic benefit based on an individual's multiomic signature may identify predictive markers of treatment success. OBJECTIVES: The primary objective of the Hmong Microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C) study was to assess the effectiveness of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The secondary objectives were to assess if 1) vitamin C impacts the taxonomic and functional patterns of microbiota; 2) taxonomic and functional patterns of microbiota impact vitamin C's urate-lowering effects; 3) genetic variations impact vitamin C's urate-lowering effects; 4) differential microbial biomarkers exist for patients with or without gout; and 5) there is an association between obesity, gut microbiota and gout/hyperuricemia. METHODS: This prospective open-labelled clinical trial was guided by community-based participatory research principles and conducted under research safety restrictions for SARS-CoV-2. We aimed to enroll a convenient sample of 180 Hmong adults (120 with gout/hyperuricemia and 60 without gout/hyperuricemia) who provided medical, demographic, dietary and anthropometric information. Participants took vitamin C 500mg twice daily for 8 weeks and provided pre-and post- samples of blood and urine for urate measurements as well as stool samples for gut microbiome. Salivary DNA was also collected for genetic markers relevant to uric acid disposition. EXPECTED RESULTS: We expected to quantify the impact of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The outcome will enhance our understanding of how gut microbiome and genomic variants impact the urate-lowering of vitamin C and associations between obesity, gut microbiota and gout/hyperuricemia. Ultimately, findings may improve our understanding of the causes and potential interventions that could be used to address health disparities in the prevalence and management of gout in this underserved population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04938024 (first posted: 06/24/2021).

A Variant Mutation in the gene encoding Mitochondrial Seryl-tRNA Synthetase Cause HUPRA Syndrome with Atypical Presentation-A Case Report (preprint)

Background Hyperuricemia, pulmonary hypertension, renal failure, and alkaline intoxication syndrome (HUPRA syndrome) is a rare autosomal recessive mitochondrial disease with prevalence of less than one in a million. Due to mutations in the mitochondrial SARS enzyme encoding seryl-tRNA synthetase on chromosome 19 (19q13.2). Case–Diagnosis/Treatment We investigated two Palestinian girls from the same village presented with progressive renal failure in infancy were diagnosed with this multisystemic disease. presented with atypical clinical manifestations of HUPRA syndrome include leukopenia, anemia, salt wasting resulting in hyponatremia and hypochloremia, renal failure with elevated blood lactate, marked hyperuricemia, hypercholesterolemia and hypertriglyceridemia but  without  pulmonary hypertension or alkaline intoxication that distinguish them from the rest of the usual cases, instead they showed acidosis in routine follow up. By using single exome sequencing analysis, we identified a two homozygous pathogenic mutation c.1175A>G (p.D392G), c.1169A>G (D390G) in SARS2 gene. This sequence identified a new variant mutation of HUPRA syndrome c.1175A>G (p.D392G) with atypical presentation, that will be added to the literature. Conclusion SARS2 gene with pathogenic homozygous mutation variants were detected in our two patients c.1175A>G (p.D392G), c.1169A>G (D390G) in exon 13, with atypical clinical manifestations of HUPRA syndrome, expanding the spectrum of SARS2 pathogenic variants with its characteristic findings, describing the differences in clinical manifestations between homozygous and compound heterozygous mutations.

U-shaped association between abnormal serum uric acid levels and COVID-19 severity: reports from the Japan COVID-19 Task Force.

OBJECTIVES: This study aimed to identify the relationship between abnormal serum uric acid levels or a history of hyperuricemia and COVID-19 severity in the Japanese population. METHODS: We included 1523 patients enrolled in the Japan COVID-19 Task Force cohort between February 2020 and May 2021. We compared the clinical characteristics, including co-morbidities, laboratory findings, and outcomes, particularly invasive mechanical ventilation (IMV), among patients with and without abnormal uric acid levels or a history of hyperuricemia. RESULTS: Patients with high serum uric acid levels were older and had higher body weight and body mass index than those without. In addition, the multiple logistic regression analysis revealed a significant association between high serum uric acid levels or a history of hyperuricemia and an increased risk of IMV (odds ratio [OR] = 1.77; P = 0.03/OR = 1.56; P = 0.04). Moreover, patients with low uric acid levels on admission were also associated significantly with the requirement of IMV (OR = 5.09; P <0.0001). CONCLUSION: Abnormal serum uric acid levels or a history of hyperuricemia were significantly associated with COVID-19 severity in the Japanese cohort.

The efficacy and adverse effects of favipiravir on patients with COVID-19: A systematic review and meta-analysis of published clinical trials and observational studies.

OBJECTIVES: This study aimed to evaluate the efficacy and adverse events of favipiravir in patients with COVID-19. METHODS: Our protocol was registered on PROSPERO (CRD42020206305). Fourteen databases were searched until February 8th, 2021. An update search for new RCTs was done on March 2nd, 2022. Meta-analysis was done for randomized controlled trials (RCTs) and non-RCTs. RESULTS: Overall, 157 studies (24 RCTs, 1 non-RCT, 21 observational studies, 2 case series, and 106 case reports) were included. On hospitalized patients, in comparison to standard of care, favipiravir showed a higher rate of viral clearance at day 5 (RR = 1.60, p = 0.02), defervescence at day 3-4 (RR = 1.99, p <0.01), chest radiological improvement (RR = 1.33, p <0.01), hospital discharge at day 10-11 (RR = 1.19, p <0.01), and shorter clinical improvement time (MD = -1.18, p = 0.05). Regarding adverse events, favipiravir groups had higher rates of hyperuricemia (RR = 9.42, p <0.01), increased alanine aminotransferase (RR = 1.35, p <0.01) but lower rates of nausea (RR = 0.42, p <0.01) and vomiting (R R= 0.19, p=0.02). There were no differences regarding mortality (RR=1.19, p=0.32), and increased aspartate aminotransferase (RR = 1.11, p = 0.25). On nonhospitalized patients, no significant differences were reported. CONCLUSIONS: Adding favipiravir to the standard of care provides better outcomes for hospitalized patients with COVID-19. Pregnant, lactating women, and patients with a history of hyperuricemia should avoid using favipiravir.

Can Uric Acid be Used as a Prognostic Factor to Determine the Severity of Covid 19 Infection.

A Novel corona virus (covid -19) was identified in 2019 in Wuhan, China. Greater proportion of patients infected by covid 19 may show signs of kidney damage. hyperuricemia has attracted greater attention. However, limited concern has been paid to the potential dangers of lowering serum uric acid. MATERIAL: this was a retrospective observational study based on 150 cases with covid 19 infection. we compared serum uric acid among two Group A - Saturation Above 90% and Group B Saturation Below 90%. Serum uric acid levels were divided into three ranges <3.5mg/dl, 3.5 to 4.5 mg/ dl and >4.5mg/dl and compared between the two groups. OBSERVATION: the age group of patients was in the range of 18years to 70 years with maximum number of patients in between the age group of 30-50 years. females constituted 32% (24), males 68% (51) belonging to group A and females 28% (21), males 72% (54) in group B. Blood urea nitrogen levels was highest in group A 77.3% (58) and the level is <40mg/dl. Serum Uric acid level <3.5 had 22.7% (17) than compared to group A having 18.7% (14). Serum uric acid level of 3.5 - 4.5 mg/dl had maximum number of patients from group B 22.7% (17) than compared to group A 16% (12). Maximum number of patients 50.7% (38) in group B had serum uric acid more than 4.5mg/dl than compared to group A 14.7% (11) accounting to a total of 33.3% (50) of the total patients. CONCLUSION: according to the observations from the data collected we can suggest that there is a possible relationship between the serum uric acid and covid severity. This retrospective study determined that the higher levels of serum uric acid levels in the critical group was higher than compared to severe group and it can be used a prognostic factor to asses the severity of outcome of covid 19 infection. this retrospective study suggested that uric acid, a purine base metabolite can be used a prognostic indicator in critically ill covid 19 patients. in the future, whether uric acid can be used to accurately reflect the viral load needs to be investigated.

Prevalence and Outcomes Associated with Hyperuricemia in Hospitalized Patients with COVID-19.

INTRODUCTION: Coronavirus 2019 (COVID-19) can increase catabolism and result in hyperuricemia. Uric acid (UA) potentially causes kidney damage by alteration of renal autoregulation, inhibition of endothelial cell proliferation, cell apoptosis, activation of the pro-inflammatory cascade, and crystal deposition. Hyperuricemia in patients with COVID-19 may contribute to acute kidney injury (AKI) and poor outcomes. METHODS: We included 834 patients with COVID-19 who were >18 years old and hospitalized for >24 h in the Mount Sinai Health System and had at least 1 measurement of serum UA. We examined the association between the first serum UA level and development of acute kidney injury (AKI, defined by KDIGO criteria), major adverse kidney events (MAKE, defined by a composite of all-cause in-hospital mortality or dialysis or 100% increase in serum creatinine from baseline), as well as markers of inflammation and cardiac injury. RESULTS: Among the 834 patients, the median age was 66 years, 42% were women, and the median first serum UA was 5.9 mg/dL (interquartile range 4.5-8.8). Overall, 60% experienced AKI, 52% experienced MAKE, and 32% died during hospitalization. After adjusting for demographics, comorbidities, and laboratory values, a doubling in serum UA was associated with increased AKI (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.9-4.1), MAKE (OR 2.5, 95% CI 1.7-3.5), and in-hospital mortality (OR 1.7, 95% CI 1.3-2.3). Higher serum UA levels were independently associated with a higher level of procalcitonin (ß, 0.6; SE 0.2) and troponin I (ß, 1.2; SE 0.2) but were not associated with serum ferritin, C-reactive protein, and interleukin-6. CONCLUSION: In patients admitted to the hospital for COVID-19, higher serum UA levels were independently associated with AKI, MAKE, and in-hospital mortality in a dose-dependent manner. In addition, hyperuricemia was associated with higher procalcitonin and troponin I levels.

Baseline uric acid levels and steady-state favipiravir concentrations are associated with occurrence of hyperuricemia among COVID-19 patients.

OBJECTIVES: Favipiravir is an antiviral that is being evaluated for the treatment of COVID-19. Use of favipiravir is associated with elevation of serum uric acid levels. Risk factors for the occurrence of hyperuricemia are unclear. METHODS: Specimens from COVID-19 patients who received 10 days of favipiravir in a previous clinical trial (jRCTs041190120) were used. Serum favipiravir concentrations were measured by LC-MS. Factors associated with the development of hyperuricemia were investigated using logistic regression analysis. Optimal cut-off values for the baseline serum uric acid levels and steady-state serum favipiravir concentrations in predicting the occurrence of hyperuricemia were determined by ROC curve analysis. RESULTS: Among the 66 COVID-19 patients who were treated with favipiravir for 10 days, the steady-state serum favipiravir concentrations were significantly correlated with serum uric acid levels. High baseline serum uric acid levels and steady-state serum favipiravir concentrations during therapy were factors associated with the development of hyperuricemia. The cut­off baseline serum uric acid level and steady-state serum favipiravir concentration during favipiravir administration determined to predict hyperuricemia were 3.7 mg/dL and 46.14 µg/mL, respectively. CONCLUSIONS: Patients with high baseline serum uric acid levels or who achieved high steady-state serum favipiravir concentrations during therapy were susceptible to hyperuricemia.

The Efficacy and Adverse Effects of Favipiravir on COVID-19 Patients: A Systematic Review and Meta-Analysis of Published Clinical Trials and Observational Studies (preprint)

Background: The burden of COVID-19 on healthcare systems worldwide requires an efficient treatment option. Favipiravir, a nucleoside analog, is a potential COVID-19 treatment. Therefore, this study aimed to evaluate the efficacy and adverse events of favipiravir in COVID-19 patients.Method: In our systematic review and meta-analysis, we performed searches of PubMed, Scopus, Embase, Web of Science, the Cochrane Library, Google Scholar, European PMC, Virtual Health Library, mRCT, ClinicalTrials.gov, SIGLE, the WHO COVID-19 research article database, Covid-evidence.org, and the iSearch COVID-19 Portfolio with the latest update on February 8 th , 2021. All types of studies in which favipiravir was used on COVID-19 patients were included and extracted by two independent authors. All studies underwent systematic review, data from controlled trials underwent meta-analysis. Our protocol was registered on PROSPERO as CRD42020206305.Findings: 145 studies (15 randomized controlled trials (RCTs), one non-RCT, 21 observational studies, two case series, and 106 case reports) were included. In comparison to standard of care (SOC), favipiravir showed a higher rate of viral clearance at day 5 (RR=1·49, p=0·03), defervescence at day 3 (RR=1·91, p<0·01), chest computed tomography (CT) improvement at day 14-15 (RR=1·40, p<0·01), and hospital discharge at day 10-11 (RR=1·31, p<0·01). Regarding adverse events, the favipiravir groups had higher rates of hyperuricemia (RR=9·42, p<0·01), but lower rates of nausea (RR=0·41, p<0·01) and vomiting (RR=0·09, p=0·02).Interpretation: Adding favipiravir to the standard of care provides better outcomes for COVID-19 patients. Pregnant and lactating women as well as a history of hyperuricemia or gouty arthritis should be noticed when using favipiravir. Using favipiravir could reduce the rate of nausea and vomiting for some patients.Registration Details: Registered on PROSPERO as CRD42020206305.Funding Information: Grant Asian clinical trial network construction project (Number JP20LK0201001J0001) by Japan Agency for Medical Research and Development (AMED).Declaration of Interests: We declare no competing interests.

Laboratory Predictors of COVID-19 Mortality: A Retrospective Analysis from Tongji Hospital in Wuhan.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly progressed to a global pandemic. Currently, there are limited effective medications approved for this deadly disease. OBJECTIVE: To investigate the potential predictors of COVID-19 mortality and risk factors for hyperinflammation in COVID-19. METHODS: Retrospective analysis was carried out in 1,149 patients diagnosed with COVID-19 in Tongji Hospital, Wuhan, China, from 1/13/2020 to 3/15/2020. RESULTS: We found significant differences in the rates of hyperuricemia (OR: 3.17, 95% CI: 2.13-4.70; p < 0.001) and hypoalbuminemia (OR: 5.68, 95% CI: 3.97-8.32; p < 0.001) between deceased and recovered patients. The percentages of hyperuricemia in deceased patients and recovered patients were 23.6% and 8.9%, respectively, which were higher than the reported age-standardized prevalence of 6.2% in Chinese population. Of note, the percentages of both IL-6 and uric acid levels in survived COVID-19 patients were above 90%, suggesting that they might be good specificity for indicators of mortality in COVID-19 patients. The serum level of uric acid (UA) was positively associated with ferritin, TNF-α, and IL-6 but not with anti-inflammatory cytokine IL-10. In addition, the levels of these proinflammatory cytokines in COVID-19 patients showed a trend of reduction after uric acid lowering therapy. CONCLUSIONS: Our results suggest that uric acid, the end product of purine metabolism, was increased in deceased patients with COVID-19. In addition, the serum level of uric acid was positively associated with inflammatory markers. Uric acid lowering therapy in COVID-19 patients with hyperuricemia may be beneficial.

Acute and severe ribavirin-associated hyperuricemia and acute kidney injury: An underrecognized adverse effect.

PURPOSE: To report a case of ribavirin-associated severe hyperuricemia in an immunocompromised patient treated for respiratory syncytial virus (RSV) infection. SUMMARY: A 21-year-old male with a past medical history of B-cell acute lymphoblastic leukemia was in full remission after allogenic bone marrow transplantation complicated with chronic graft-versus-host disease. He was hospitalized due to fever, malaise, and respiratory symptoms. A diagnosis of RSV upper respiratory tract infection complicated by secondary pneumonia was made, and oral ribavirin (600 mg in 3 divided doses daily) and intravenous levofloxacin (750 mg once daily) were initiated. On day 2 of the hospital admission, the patient's uric acid levels had increased from a baseline of 4 to 6 mg/dL to 19.3 and 22.2 mg/dL after the fourth and fifth doses of ribavirin, respectively, and his serum creatinine steadily had increased from a baseline of 0.7 to 0.8 mg/dL to 1.6 mg/dL. Ribavirin was discontinued after the sixth dose, and a single dose of intravenous rasburicase (7.5 mg) was administered. On day 3, the patient's serum uric and creatinine concentrations had decreased to 4.7 mg/dL and 1.1 mg/dL, respectively. He continued to recover on antibiotics and was discharged with normal uric acid and serum creatinine levels. CONCLUSION: We report a case of severe hyperuricemia and acute kidney injury that developed early after initiation of ribavirin for RSV infection and suspected bacterial pneumonia in an immunocompromised patient without hepatitis C, requiring ribavirin discontinuation and rasburicase administration. To our knowledge, this is the first reported case of severe hyperuricemia in a patient treated with ribavirin for RSV infection rather than chronic hepatitis C. Clinicians should be aware of the possibility of acute and severe hyperuricemia following ribavirin administration.

Gout Pharmacotherapy in Cardiovascular Diseases: A Review of Utility and Outcomes.

Hyperuricemia and gout have been linked to an increased risk for cardiovascular (CV) disease, stroke, hypertension, heart failure, and chronic kidney disease, possibly through a proinflammatory milieu. However, not all the drugs used in gout treatment improve CV outcomes; colchicine has shown improved CV outcomes in patients with recent myocardial infarction and stable coronary artery disease independent of lipid-lowering effects. There is resurging interest in colchicine following publication of the COLCOT, LoDoCo, LoDoCo2, LoDoCo-MI trials, and COLCORONA trial which will shed light on its utility in COVID-19. Our aim is to review the CV use of colchicine beyond pericardial diseases, as well as CV outcomes of the available gout therapies, including allopurinol and febuxostat. The CARES trial and its surrounding controversies, which lead to the US FDA 'black box' warning on febuxostat, in addition to the recent FAST trial which contradicts this and finds febuxostat to be non-inferior, are discussed in this paper.

A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19.

Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (in the latter case, the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76 to 2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, times to defervescence were 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95% CI, 0.81 to 4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by reverse transcription-PCR (RT-PCR) by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation. (This study has been registered with the Japan Registry of Clinical Trials under number jRCTs041190120.).

Association of Serum Uric Acid Levels with COVID-19 Severity (preprint)

Aims: Hyperuricemia has attracted increasing attention, however, limited attention has been paid to the potential dangers of lowering serum uric acid (SUA). We observed lower levels of SUA in COVID-19 patients. Therefore, we aim to explore the SUA levels in COVID-19 patients and the relationship between SUA and the severity of COVID-19. Methods: A case-control study based on 91 cases with COVID-19 and 1:3 age- and sex-matched healthy control subjects (N=273) were included. We firstly compared the SUA levels and the uric acid/creatinine (UA/Cr) ratio between COVID-19 patients and the healthy controls. Then, we examined the association of the SUA levels and UA/Cr ratios with COVID-19 severity defined according to the fifth edition of China’s Diagnosis and Treatment Guidelines of COVID-19. Results: SUA levels at admission were 2.59% lower, UA/Cr ratios 6.06% lower in COVID-19 patients compared to controls. In sex stratified analysis, SUA and UA/Cr were lower in male COVID-19 patients while only SUA was lower in female COVID-19 patient. Moreover, SUA and UA/Cr values were 4.27% and 8.23% lower in the severe group than in the moderate group among male COVID patients. A multiple linear regression analysis showed that SARS-CoV-2 infection and male sex were independent factors associated with lower SUA levels. COVID-19 male patients with low SUA levels at had higher risk of developing severe symptoms than those with high SUA levels (incidence rate ratio: 4.05; 95% CI:1.11，14.72) at admission. After completion of the first follow-up of the COVID-19 patients within 1-3 weeks after discharge, we found that male patients experienced severe symptoms had significantly lower SUA and UA/Cr ratio levels comparing to moderate patients but no significant difference between different time points. In females, female patients have both SUA and UA/Cr ratio levels lower at discharge than that at admission, however these differences disappear at follow-up exam.Conclusion: COVID-19 patients had SUA and UA/Cr values lower than normal at admission. Male COVID-19 patients with low SUA levels had a significantly higher risk of developing severe symptoms than those with high SUA levels. During the aggravation course of the disease, the level of SUA gradually decreased until discharge. At follow-up exam, the level of SUA is similar to the levels at admission.

Association of serum uric acid levels with COVID-19 severity (preprint)

Aims: Hyperuricemia has attracted increasing attention, however, limited attention has been paid to the potential dangers of lowering serum uric acid (SUA). We observed lower levels of SUA in COVID-19 patients. Therefore, we aim to explore the SUA levels in COVID-19 patients and the relationship between SUA and the severity of COVID-19.Methods: A case-control study based on 91 cases with COVID-19 and 1:3 age- and sex-matched healthy control subjects (N = 273) were included. We firstly compared the SUA levels and the uric acid/creatinine (UA/Cr) ratio between COVID-19 patients and the healthy controls. Then, we examined the association of the SUA levels and UA/Cr ratios with COVID-19 severity defined according to the fifth edition of China’s Diagnosis and Treatment Guidelines of COVID-19.Results: SUA levels at admission were 2.59% lower, UA/Cr ratios 6.06% lower in COVID-19 patients compared to controls. In sex stratified analysis, SUA and UA/Cr were lower in male COVID-19 patients while only SUA was lower in female COVID-19 patient. Moreover, SUA and UA/Cr values were 4.27% and 8.23% lower in the severe group than in the moderate group among male COVID patients. A multiple linear regression analysis showed that SARS-CoV-2 infection and male sex were independent factors associated with lower SUA levels. COVID-19 male patients with low SUA levels at had higher risk of developing severe symptoms than those with high SUA levels (incidence rate ratio: 4.05; 95% CI:1.11,14.72) at admission. After completion of the first follow-up of the COVID-19 patients within 1–3 weeks after discharge, we found that male patients experienced severe symptoms had significantly lower SUA and UA/Cr ratio levels comparing to moderate patients but no significant difference between different time points. In females, female patients have both SUA and UA/Cr ratio levels lower at discharge than that at admission, however these differences disappear at follow-up exam.Conclusion: COVID-19 patients had SUA and UA/Cr values lower than normal at admission. Male COVID-19 patients with low SUA levels had a significantly higher risk of developing severe symptoms than those with high SUA levels. During the aggravation course of the disease, the level of SUA gradually decreased until discharge. At follow-up exam, the level of SUA is similar to the levels at admission.

Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19 (preprint)

Background: Favipiravir is an antiviral drug, an inhibitor of RNA dependent RNA polymerase that is preliminarily effective against SARS-CoV-2 virus. The aim of this study was to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate coronavirus disease (COVID-19).Methods: We conducted an open-labeled, randomized, active-controlled multicenter trial of an oral dosage form of favipiravir in out- and hospitalized patients with mild to moderate COVID-19. The study was organized in 10 clinical centers in Russia. Eligible patients had laboratory confirmed by PCR test infection of SARS-CoV-2 and were aged 18-60 years. Patients were randomly assigned (in a 2:1 ratio) to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for up to 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine) for up to 10 days. Randomization was performed using a web-response system after stratification by COVID-19 severity, age and CT severity at enrollment. The co-primary outcomes were the time to clinical improvement and the time to viral clearance. An efficacy analysis was performed in intent-to-treat population. The safety population included all participants who received at least one dose of favipiravir or SOC. Findings: Between May 23, 2020, and June 30, 2020, 190 patients were assessed for eligibility, of whom 168 were randomly assigned to receive either favipiravir (n = 112), or SOC (n = 56). The median time to clinical improvement was 6.0 (IQR 4·0; 9·3) days in favipiravir group and 10.0 (IQR 5·0; 21·0) days in SOC group; the median difference was 4 days (HR 1·63; 95% CI 1·14-2·34, p = 0·007). The statistically significant difference in the median time to viral clearance was observed only in the hospitalized cohort of patients: 3·0 (IQR 3·0; 3·0) vs. 5·0 (IQR 4·5; 5·5), respectively (HR 2·11; 95% CI 1·04-4·31; p = 0·038). However, the rate of viral elimination on Day 5 in the favipiravir group was significantly higher in the whole population: 81·2% vs. 67·9% respectively (RR 1·22; 05% CI 1·00-1·48; p = 0.022). The rate of clinical improvement on Day 7 in the favipiravir group was 1.5-fold higher compared to SOC: 52·7% vs. 35·8% (RR 1·50; 95% CI 1·02-2·22; p = 0·020). Favipiravir was well tolerated: most of the adverse events (AE) were mild. Any AEs were reported in 74·1% of patients in the favipiravir group vs. 60·0% in the SOC group. Among the most common adverse reactions was asymptomatic hyperuricemia, transient elevation of ALT & AST, and gastrointestinal disorders (diarrhea, nausea, abdominal pain).Interpretation: Favipiravir was superior to SOC in shortening the time to clinical improvement in patients with mild to moderate COVID-19.Trial Registration: The trial is registered on ClinicalTrials.gov, identifier: NCT04501783.Funding: Funded by R-Pharm Group of CompaniesDeclaration of Interests: ENK, MYS, MVN, VAR, AVZ, and OVF were employees of R-Pharm Group of Companies during the study and received compensation as part of their employment. All other authors declare no competing interests.Ethics Approval Statement: The trial protocol was approved by the Russian Ministry of Health (MoH) (permission #201 dated by May 20, 202010), including Central Ethics Council, and by the appropriate local ethics committees at each center. Enrollment in this trial was done on the10 trial sites in Russia, including hospitals and outpatient sites. All of the patients provided written informed consent (IC) before the enrollment.

Acute Gouty Arthritis During Favipiravir Treatment for Coronavirus Disease 2019.

A 42-year-old man exhibiting hypoxia was diagnosed with coronavirus disease 2019. He had medical histories of type 2 diabetes, hyperlipidemia, hyperuricemia, and gout attack. He received favipiravir for compassionate use for 14 days. Subsequently, he showed increased uric acid levels and developed acute gouty arthritis. Favipiravir may induce not only hyperuricemia but also acute gouty arthritis. It should therefore be used with caution in patients with a history of gout and those with hyperuricemia, especially when used at a higher dose and for a longer duration than is typical.

Uric Acid Elevation by Favipiravir, an Antiviral Drug.

In light of the recent pandemic, favipiravir (Avigan®), a purine nucleic acid analog and antiviral agent approved for use in influenza in Japan, is being studied for the treatment of coronavirus disease 2019 (COVID-19). Increase in blood uric acid level is a frequent side effect of favipiravir. Here, we discussed the mechanism of blood uric acid elevation during favipiravir treatment. Favipiravir is metabolized to an inactive metabolite M1 by aldehyde oxidase and xanthine oxidase, and excreted into urine. In the kidney, uric acid handling is regulated by the balance of reabsorption and tubular secretion in the proximal tubules. Favipiravir and M1 act as moderate inhibitors of organic anion transporter 1 and 3 (OAT1 and OAT3), which are involved in uric acid excretion in the kidney. In addition, M1 enhances uric acid reuptake via urate transporter 1 (URAT1) in the renal proximal tubules. Thus, favipiravir is thought to decrease uric acid excretion into urine, resulting in elevation of uric acid levels in blood. Elevated uric acid levels were returned to normal after discontinuation of favipiravir, and favipiravir is not used for long periods of time for the treatment of viral infection. Thus, the effect on blood uric acid levels was subclinical in most studies. Nevertheless, the adverse effect of favipiravir might be clinically important in patients with a history of gout, hyperuricemia, kidney function impairment (in which blood concentration of M1 increases), and where there is concomitant use of other drugs affecting blood uric acid elevation.