Abstract
Background: Hyperuricemia is associated with several risk factors for mortality and severe coronavirus disease 2019 (COVID-19) manifestations.
Objective: The objective of this research was to examine whether hyperuricemia is a risk factor for mortality and other adverse outcomes in patients hospitalized for COVID-19.
Design: This is a retrospective review of patients hospitalized for COVID-19 between March 15 and November 30, 2020, with available uric acid (UA) levels.
Results: Among 1566 patients who were hospitalized during the study period, 222 patients had an available UA level. The mean age ± standard deviation (SD) was 56.5 ± 19.5 years. The mean ± SD for UA (mg/dL) among the total cohort was 5.65 ± 2.18, and 21.2% of the total study population had hyperuricemia (UA > 7 mg/dL) on admission. The mortality rate was 14.4%, and mortality was associated with higher UA levels on admission (6.9 ± 2.6 mg/dL vs. 5.5 ± 2 mg/dL in patients who survived, P < 0.05). Patients who needed intensive oxygen support (high-flow nasal cannula or mechanical ventilation) and those who required longer-than-average hospitalization (> 7 days) had more hyperuricemia (intensive oxygen support: 30% vs. 18%, P = 0.07; long hospitalization 29% vs. 16.2%, P < 0.05).
Conclusion: Our findings show that high UA levels are associated with adverse outcomes in patients hospitalized for COVID-19. We suggest evaluating hyperuricemia as a marker that integrates and reflects both poor prognostic baseline characteristics and acute components such as inflammatory state, hypovolemic state, and renal failure.
Keywords: COVID-19; Hyperuricemia, Mortality; Uric acid
Since the emergence of coronavirus disease 2019 (COVID-19), several risk factors for severity and mortality in hospitalized patients have been identified and described. These include older age, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), hypertension (HTN), diabetic mellitus (DM), obesity, high lactate dehydrogenase (LDH), high C-reactive protein (CRP), and low lymphocyte count on admission.1-5
Uric acid (UA) is an organic compound, a product of purine metabolism in the enzymatic cascade when hypoxanthine is oxidized to xanthine and then to UA by the enzyme xanthine oxidase. Normal values of serum UA are 1.5–6.0 mg/dL in women and 2.5–7.0 mg/dL in men. The most common disease associated with hyperuricemia is gout, other conditions include kidney stones and tophi. Previous studies have shown hyperuricemia is associated with CKD, HTN, obesity, dyslipidemia, and metabolic syndrome.6,7 In addition, hyperuricemia is associated with poor prognosis in viral diseases such as hepatitis C8 and Hepatitis B.9 Moreover, it has been shown that hyperuricemia on admission to the internal medicine department, for any diagnosis, is a risk factor for short- and long-term mortality.10,11 On the other hand, UA has antioxidant effects, and a high UA level is considered to be one of the main antioxidants that protects cells from oxidative damage.12,13 Interestingly, several retrospective studies have shown that among patients hospitalized for COVID-19, hypouricemia on admissions is associated with short-term mortality.14-17 He et al18 found patients with severe cases of COVID-19 had very low UA levels. However, there are scarce data regarding the association between hyperuricemia mortality and other outcomes in patients with COVID-19. The objective of this study was to examine whether hyperuricemia on admission is associated with mortality and other adverse outcomes in patients hospitalized for COVID-19.
As hyperuricemia is associated with many risk factors for mortality and severity in COVID-19 patients, and based on our previous studies that have established an association between hyperuricemia and short- and long-term mortality among hospitalized patients,10,11 our baseline prediction was that UA level on admission is associated with mortality and morbidity in hospitalized COVID-19 patient.
Methods
The study was conducted at the Shaare Zedek Medical Center, a 1000-bed university-affiliated tertiary care center. It is one of two major medical centers serving the Jerusalem area’s population of 1 million people. During the COVID-19 pandemic, it has served as a specialized center for patients with COVID-19.
We conducted a retrospective study of all patients admitted with a COVID-19 diagnosis between March 15 and November 30, 2020 who had available UA blood test results drawn during the first 4 days of admission. Patients were divided according to primary outcomes. The UA level and relevant demographic, clinical, and laboratory data were compared between the groups. As the definition of hyperuricemia is still in dispute, we have chosen to use a cut-off level of UA > 7mg/dL, which is universally accepted as indicative of hyperuricemia. The Norton Scale score (NSS) on admission was used to evaluate the general condition of the patients. This scale, ranging from a minimum of 4 to a maximum of 20 points, facilitates assessment of physical and mental conditions, activity, mobility, and incontinence.17
The primary outcomes were mortality, the need for high-flow nasal cannula (HFNC) or mechanical ventilation, COVID-19 severity (mild and moderate versus severe and critical), and the length of hospitalization (LOH). The severity of disease was categorized according to the National Institutes of Health (NIH): Asymptomatic or mild – patients without symptoms or those who have any sign but without shortness of breath, dyspnea, or abnormal chest imaging; Moderate – patients with evidence of lower respiratory disease during clinical assessment or imaging but without hypoxia; Severe – patients with hypoxia on room air (SpO2 < 94); and Critical – patients who have respiratory failure, septic shock, and/or multiple organ dysfunction.18
Statistical Analysis
The UA level, clinical, and laboratory data were compared according to outcomes. Categorical variables were compared by using the χ2 test, and continuous variable means were compared by using Student’s t-test. The cut-off level for statistical analysis for a difference between the groups was P < 0.05. Univariate linear regression was performed to explore the correlation between two continuous variables. Multivariate logistic regression was performed to find the predictive factors for outcomes. All statistical data were calculated by using SPSS Statistics version 23. The study was approved by the Medical Center’s internal review board, the Helsinki Committee, which provided a waiver from obtaining informed consent based on the retrospective and non-interventional study design.
Results
Among 1566 patients who were hospitalized for COVID-19 during the study period, in 222 patients UA level was available. The mean ± standard deviation [SD] age was 56.6 ± 19.5 years, and 83 patients (37.4%) were ≥ 65 years old. Regarding gender, 56.8% were male and 43.2% were female. The average ± SD serum UA level was 5.65 ± 2.18 mg/dL; 77 (34.7%) and 47 patients (21.2%) had a UA level > 6 mg/dL and > 7 mg/dL, respectively. Demographic, clinical, and laboratory characteristics of the study population on admission are summarized in Table 1.
Table 1.
Demographic data, comorbidity, laboratory characteristics and primary outcomes
| Mortality | Oxygen support | Disease severity | Length of hospitalization (LOH) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total population (N = 222) |
Alive (n = 190) |
Death (n = 32) |
P | Room air or nasal canula (n = 159) |
Need for HFNC or invasive ventilation (n = 53) |
P | Mild and moderate (n = 100) |
Severe and critical (n = 122) |
P | LOH < 7 (n = 128) |
LOH > 7 (n = 128) |
P | |
| Age, mean ± SD | 56.6 ± 19.5 | 53.4 ± 19.0 | 74.9 ± 10.3 | 0.00 | 53.4 ± 19.9 | 66.4 ± 14.5 | 0.00 | 53.9 ± 20.2 | 58.8 ± 18.7 | 0.07 | 50.3 ± 19.3 | 66.7 ± 15.2 | 0.00 |
| Gender % | |||||||||||||
| Male | 56.8 | 78.6 | 21.4 | 0.09 | 50.3 | 77.4 | 0.00 | 67.5 | 32.5 | 0.00 | 50.0 | 62.9 | |
| Female | 43.2 | 89.6 | 10.4 | 49.7 | 22.6 | 49.7 | 22.6 | 73.6 | 26.4 | 0.13 | |||
| Smoker % | 7.7 | 5.3 | 21.9 | 0.04 | 6.5 | 11.3 | 0.25 | 6.0 | 9.0 | 0.56 | 5.5 | 4.8 | 0.58 |
| NSS, mean ± SD | 17.6 ± 3.7 | 0.00 | 18.0 | 16.1 | 0.00 | 18.8 ± 2.5 | 16.5 ± 4.2 | 0.00 | 18.4 ± 3.0 | 16.2 ± 4.3 | 0.00 | ||
| BMI, mean ± SD | 26.6 ± 8.1 | 29.7 ± 8.4 | 29.7 ± 6.9 | 0.98 | 28.8 ± 6.7 | 32.1 ± 10.9 | 0.01 | 29.6 ± 8.6 | 29.7 ± 7.8 | 0.88 | 28.9 ± 7.0 | 31.0 ± 10.4 | 0.17 |
| Morbidity - Disease % | |||||||||||||
| Overweight | 67.1 | 66.3 | 71.9 | 0.68 | 64.5 | 75.5 | 0.39 | 56.0 | 76.0 | 0.00 | 66.9 | 67.4 | 0.93 |
| Morbid obesity | 35.1 | 13.9 | 15.4 | 0.92 | 30.2 | 50.9 | 0.01 | 26.0 | 42.6 | 0.02 | |||
| Dyslipidemia | 20.3 | 11.9 | 29.4 | 0.06 | 18.9 | 24.5 | 0.49 | 15.0 | 24.6 | 0.11 | 18.4 | 23.3 | 0.4 |
| DM | 34.7 | 33.2 | 43.8 | 0.34 | 32 | 43.4 | 0.17 | 27.0 | 41.0 | 0.04 | 30.1 | 41.9 | 0.1 |
| CHF | 7.7 | 6.3 | 15.6 | 0.07 | 7.7 | 7.5 | 0.99 | 7.0 | 8.2 | 0.93 | 5.9 | 10.5 | 0.32 |
| COPD | 11 | 3.2 | 15.6 | 0.01 | 4.1 | 7.5 | 0.53 | 3.0 | 6.6 | 0.37 | 5.1 | 4.7 | 0.87 |
| IHD | 13.1 | 9.5 | 34.4 | 0.00 | 11.8 | 17.0 | 0.46 | 9.0 | 16.4 | 0.15 | 9.6 | 18.6 | 0.08 |
| CKI | 9.0 | 7.4 | 18.8 | 0.08 | 9.5 | 4.0 | 0.88 | 4.0 | 13.1 | 0.03 | 5.9 | 14 | 0.07 |
| HTN | 45.9 | 41.1 | 75.0 | 0.00 | 39.6 | 66.0 | 0.00 | 35.0 | 54.9 | 0.00 | 40.4 | 54.7 | 0.05 |
| Hyperuricemia on admission | 21.2 | 31.6 | 53.1 | 0.03 | 18.3 | 30.2 | 0.07 | 19.6 | 22.4 | 0.73 | 16.2 | 29.1 | <0.05 |
| Laboratory values, mean ± SD | |||||||||||||
| Uric acid (mg/dL) | 5.65 ± 2.18 | 5.5 ± 20 | 6.9 ± 2.6 | 0.01 | 5.5 ± 2.0 | 6.1 ± 2.5 | 0.1 | 5.85 ± 2.46 | 5.4 ± 1.8 | 0.12 | 5.4 ± 2.0 | 6.1 ± 2.4 | 0.02 |
| BUN (mg/dL) | 22.3 ± 20.3 | 19.2 ± 17.5 | 40.5 ± 25.8 | 0.00 | 19.6 ± 18.5 | 30.9 ± 23.4 | 15.4 ± 13.1 | 27.9 ± 23.3 | 0.00 | 17.7 ± 16.8 | 29.6 ± 23.2 | 0.00 | |
| GFR | 93 ± 58 | 98.7 ± 57.9 | 57.5 ± 42.9.5 | 0.00 | 105 ± 64 | 94 ± 53 | 0.15 | 101 ± 61.1 | 85 ± 5.0 | 0.036 | 101 ± 60 | 79 ± 51 | 0.01 |
| LDH (IU/L) | 363 ± 330 | 319 ± 177 | 587 ± 674 | 0.04 | 304 ± 320 | 525 ± 304 | 0.00 | 243(69) | 450 ± 409 | 0.00 | 318 ± 381 | 427 ± 229 | 0.03 |
| ALP (IU/L) | 85 ± 67 | 83.4 ± 68.8 | 92.6 ± 57.4 | 0.49 | 82.6 ± 51.8 | 91.3 ± 98.3 | 0.43 | 86 ± 57 | 84 ± 74 | 0.82 | 80 ± 48 | 92 ± 88 | 0.3 |
| GGT (IU/L) | 64 ± 103 | 61 ± 103 | 79 ± 108 | 0.38 | 61.7 ± 107.5 | 70.4 ± 92.2 | 0.61 | 55 ± 98 | 70 ± 108 | 0.32 | 55 ± 85 | 77 ± 126 | 0.17 |
| ALT (IU/L) | 37 ± 93 | 28 ± 25 | 86 ± 219 | 0.15 | 37.2 ± 105.5 | 37.2 ± 43.0 | 0.99 | 25 ± 19 | 46 ± 121 | 0.07 | 37 ± 116 | 37 ± 42 | 0.98 |
| AST (IU/L) | 64 ± 219 | 39 ± 33 | 193 ± 526 | 0.11 | 59.7 ± 248.0 | 77.5 ± 103.7 | 0.62 | 33 ± 24 | 88 ± 287 | 0.049 | 64 ± 277 | 64 ± 87 | 0.99 |
| Total bilirubin (mg/dL) | 0.60 ± 0.79 | 0.55 ± 0.68 | 0.88 ± 1.18 | 0.14 | 0.6 ± 0.9 | 0.6 ± 0.5 | 0.99 | 0.6 ± 1.0 | 0.6 ± 0.6 | 0.63 | 0.55 ± 0.72 | 0.66 ± 0.88 | 0.99 |
| Total protein (mg/dL) | 7.4 ± 4.3 | 7.6 ± 4.7 | 6.11 ± 1.05 | 0.22 | 7.7 ± 5.2 | 6.6 ± 1.1 | 0.22 | 8.4 ± 7.0 | 6.7 ± 1.0 | 0.054 | 8 ± 5.9 | 6.7 ± 0.9 | 0.15 |
| Albumin (mg/dL) | 3.8 ± 2.9 | 3.95 ± 3.12 | 2.95 ± 0.5 | 0.14 | 4.0 ± 3.3 | 3.0 ± 0.5 | 0.06 | 4.5 ± 4.3 | 3.3 ± 0.7 | 0.03 | 4.3 ± 3.8 | 3.2 ± 0.6 | 0.05 |
| WBC (103/uL) | 7.43 ± 4.44 | 6.6 ± 13.2 | 12.2 ± 7.2 | 0.00 | 6.5 ± 2.9 | 10.5 ± 6.6 | 0.00 | 6 ± 2.4 | 8.6 ± 5.3 | 0.00 | 6.8 ± 4.0 | 8.4 ± 4.9 | 0.01 |
| Hemoglobin (g/dL) | 12.7 ± 2.3 | 12.8 ± 2.2 | 12.05 ± 2.4 | 0.09 | 12.8 ± 2.3 | 12.3 ± 2.2 | 0.17 | 13.1 ± 2.3 | 12.3 ± 2.2 | 0.00 | 13.0 ± 2.3 | 12.1 ± 2.1 | 0.00 |
| Platelets (103/uL) | 207 ± 88 | 203 ± 78 | 231 ± 132 | 0.26 | 204 ± 78 | 216 ± 115 | 0.47 | 199 ± 63 | 213 ± 104 | 0.22 | 208 ± 85 | 206 ± 64 | 0.88 |
| Lymphocytes (103/uL) | 1.26 ± 0.7 | 1.32 ± 0.67 | 0.9 ± 0.47 | 0.00 | 1.4 ± 0.67 | 0.88 ± 0.45 | 0.00 | 1.6 ± 0.71 | 0.98 ± 0.46 | 0.00 | 1.42 ± 0.7 | 1.0 ± 0.6 | 0.00 |
| CRP mg/dL | 8.34 ± 8.42 | 7.4 ± 8.1 | 14.2 ± 8.4 | 0.00 | 5.9 ± 6.6 | 15.9 ± 8.9 | 0.00 | 3.5 ± 4.7 | 12.2 ± 8.7 | 0.00 | 5.8 ± 6.82 | 12.42 ± 9.12 | 0.00 |
| D-dimer | 3991 ± 13807 | 2892 ± 11595 | 10159 ± 22022 | 0.19 | 911 ± 1175 | 10818 ± 23500 | 0.01 | 713 ± 648 | 6715 ± 18291 | 0.01 | 3273 ± 14311 | 5132 ± 13041 | 0.48 |
| Fibrinogen | 677 ± 578 | 678 ± 630 | 683 ± 210 | 0.96 | 650 ± 686 | 737 ± 177 | 0.45 | 647 ± 859 | 701 ± 163 | 0.62 | 663 ± 724 | 700 ± 189 | 0.74 |
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; BUN, blood urea nitrogen; CHF, congestive heart failure; CKI, chronic kidney injury; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; HFNC, high-flow nasal canula; HTN, hypertension; IHD, ischemic heart disease; LDH, lactate dehydrogenase; NSS, Norton scale score; SD, standard deviation; WBC, white blood cells
As noted above, 21.2% of total study population had hyperuricemia (UA > 7 mg/dL) on admission. In multivariate analysis, the strongest factors associated independently with hyperuricemia were congestive heart failure (CHF; odds ratio [OR] = 8.4, 95% confidence interval [CI] 1.8–38.6), smoking (OR = 6.56, 95% CI 1.29–33.45), morbid obesity (OR = 3.65, 95% CI 1.33–9.98), and white blood count (WBC) and blood urea nitrogen (BUN) on admission (Table 2).
Table 2.
Multivariate factors associated with hyperuricemia on admission in patients hospitalized for COVID-19
| Risk factors for hyperuricemia on admission | Odds ratio (95% CI) | P |
|---|---|---|
| Congestive heart failure | 8.4 (1.8–38.6) | 0.00 |
| Blood urea nitrogen | 1.05 (1.03–1.08) | 0.00 |
| White blood count | 1.13 (1.03–1.24) | 0.01 |
| Morbid obesity | 3.65 (1.33–9.98) | 0.01 |
| Smoker | 6.56 (1.29–33.45) | 0.02 |
The mortality rate was 14.4% and was associated with a higher UA level on admission (6.9 ± 2.6 mg/dL vs. 5.5 ± 2 mg/dL in patients who did not die, P < 0.05). In univariate analysis, risk factors for mortality during hospitalization were hyperuricemia (OR = 3.14, 95% CI 1.47–6.97), older age (> 65 years old, OR = 17.18, 95% CI 5.76–51.28), smoking (OR = 5.04, 95% CI 1.76–14.44), dyslipidemia (OR = 2.40, 95% CI 1.06–4.45), HTN (OR = 4.30, 95% CI 1.84–10.09), ischemic heart disease (IHD; OR = 5.00, 95% CI 2.08–12.02), COPD (OR = 5.68, 95% CI 1.62–6.19), lymphopenia (< 1×103/uL; OR = 3.28, 95% CI 1.54–7.42), leukocytosis (> 11×103/uL; OR = 9.15, 95% CI 2.85–21.7), high CRP (> 10 mg/dL; OR = 6.03, 95% CI 2.63–13.84), and NSS < 15 (OR = 14.73, 95% CI 5.89–36.8, Table 3).
Table 3.
Risk factors for mortality in patients hospitalized for COVID-19
| Risk factors for mortality | P | Odds ratio (95% CI) |
|---|---|---|
| Univariate analysis | ||
| Hyperuricemia | 0.01 | 3.14 (1.42–6.97) |
| Older age | 0.00 | 17.18 (5.76–51.28) |
| Male | 0.2 | 2.16 (0.95–4.91) |
| Morbid obesity | 0.8 | 1.13 (0.52–2.45) |
| Smoker | 0.00 | 5.04 (1.76–14.44) |
| Dyslipidemia | 0.04 | 2.40(1.06–4.45) |
| DM | 0.7 | 1.56 (0.73–3.36) |
| CHF | 0.8 | 2.75(0.9–8.4) |
| HTN | 0.01 | 4.30(1.84–10.09) |
| IHD | 0.00 | 5.00(2.08–12.02) |
| COPD | 0.01 | 5.68(1.62–19.90) |
| Lymphopenia (< 1× 103/uL) | 0.00 | 3.38 (1.54–7.42) |
| Leukocytosis (> 11 × 103/uL) | 0.00 | 9.15 (2.85–21.70) |
| CRP >10 mg/dL | 0.00 | 6.03 (2.63–13.84) |
| Functional and cognitive impairment on admission | 0.00 | 14.73(5.89–36.80) |
| Multivariate analysis | ||
| Older age | 0.01 | 10.72 (1.75–65.54) |
| Male | 0.00 | 14.51 (2.33–90.46) |
| IHD | 0.02 | 6.75 (1.32–34.53) |
| Leukocytosis | 0.00 | 10.82 (2.21–52.94) |
| CRP > 10 mg/dL | 0.03 | 4.68 (1.18–18.53) |
| Functional and cognitive impairment on admission | 0.00 | 20.19 (3.67–111) |
DM, diabetes mellitus; CHF, congestive heart failure; HTN, hypertension; IHD, ischemic heart disease; COPD, chronic obstructive heart disease; CRP, C-reacitve protein
In multivariate analysis, older age (> 65 years; OR = 10.72, 95% CI 1.75–65.54), male gender (OR = 14.51, 95% CI 2.33–90.46), IHD (OR = 6.75, 95% CI 1.32–34.53), leukocytosis (OR = 10.82, 95% CI 2.21–52.94), high CRP (OR = 4.69, 95% CI 1.18–18.53), and low NSS (OR = 20.19, 95% CI 3.67–111) were found to predict mortality (Table 3).
Disease severity was mild in 85 patients (38.3%), moderate in 15 patients (6.8%), severe in 93 patients (41.9%), and critical in 29 patients (13.1%). The percentage of patients with hyperuricemia, DM, CRF, HTN, and overweight was higher among patients with moderate-severe disease, and they had a lower NSS score; higher CRP and D-dimer levels; and lower glomerular filtration rate (GFR), alanine transaminase (ALT), aspartate transaminase (AST), albumin, hemoglobin, and lymphocyte levels on admission (Table 1). Based on multivariate analysis, high BUN, high CRP (OR = 7.78, 95% CI 2.83–21.42), lymphopenia (OR = 4.02, 95% CI 1.89–8.56), and overweight (OR = 3.48, 95% CI 1.62–7.44) were associated with severe-critical disease (Table 4).
Table 4.
Multivariate factors associated with intensive oxygenation support, disease severity, and length of hospitalization > 7 days in patients hospitalized for COVID-19
| Odds ratio (95% CI) | P | |
|---|---|---|
| Intensive oxygenation support | ||
| Morbid obesity | 4.24 (1.45–12.34) | 0.01 |
| HTN | 3.35 (1.20–9.30) | 0.00 |
| CRP >10 | 2.00 (1.24–9.84) | 0.01 |
| Moderate or severe disease | ||
| BUN | 1.01 (1.00–1.05) | 0.01 |
| CRP >10 mg/dL | 7.78(2.83–21.42) | 0.00 |
| Lymphopenia | 4.02(1.89–8.56) | 0.00 |
| Overweight | 3.48 (1.62–7.44) | 0.00 |
| Length of hospitalization > 7 days | ||
| Older age | 5.8 (2.61–12.94) | 0.01 |
| CRP > 10 mg/dL | 6.8 (2.8–16.47) | 0.01 |
HTN, hypertension; ICRP, C-reacitve protein; BUN, blood urea nitrogen
Of the total cohort, 53 patients (23.9%) required HFNC or mechanical ventilation support during their hospitalization. These patients were older and mostly male, and there was a high percentage of morbid obesity, HTN, and hyperuricemia. Their laboratory results showed higher BUN, LDH, WBC, CRP, and D-dimer levels, and a lower lymphocyte count (Table 1). In multivariate analysis, morbid obesity (OR = 34.24, 95% CI 1.45–12.34), HTN (OR = 3.48, 95% CI 1.62–7.44) and high CRP (OR = 2.00, 95% CI 1.62–7.44) were associated with intensive oxygen support (Table 4).
The mean ± SD LOH was 10.8 ± 15.8 days. Patients with a long LOH (> 7 days) were older; had a lower NSS; and had a high percentage of CKD, HTN, and hyperuricemia. The laboratory results of patients who needed longer hospitalization showed higher UA, BUN, LDH, and CRP levels, a lower lymphocyte count, as well as lower GFR, albumin, and hemoglobin levels (Table 1). In multivariate analysis, older age (OR = 5.8, 95% CI 2.61–12.94) and high CRP were associated with LOH > 7 days (Table 4).
Discussion
Hyperuricemia is associated with the same known risk factors for morbidity and severity in patients with COVID-19.1-7 UA level has been found to be associated with adverse outcomes in various acute clinical settings: coronary artery disease,21,22 preeclampsia,23 febrile neutropenia,24 COPD,25 and in patients hospitalized in the internal medicine department (regardless of the reason for hospitalization).7 On the other hand, there are data on the beneficial effect of UA as an antioxidant,13 and several studies have shown that hypouricemia is associated with a poor outcome among patients with COVID-19.15 In this study, we examined whether a high UA level is associated with mortality and other adverse outcomes in patients hospitalized for COVID-19. The mean UA level was 5.65 mg/dL, which is in the high-normal range. As expected, the average UA level was higher among males in comparison with females (6.1 and 5.1 mg/dL, respectively, P < 0.05). Compared to our prior study of patients hospitalized in internal medicine wards in the same medical institution, the percentage of patients with hyperuricemia was lower (21.2% vs 28%), and mortality rate among patient with hyperuricemia was slightly lower (6.9% vs 7.7%). However, in this study the cut-off for hyperuricemia was lower (7 vs. 7.5 mg/dL), the average UA level was lower (5.6 vs 6.3 mg/dL), the mean age was lower (56 vs. 78 years), and all patients had the same admitting diagnosis (COVID-19).8
Baseline characteristics that were associated independently with hyperuricemia were CHF, morbid obesity, and smoking status. These factors are consistent with previous data regarding risk factors associated with hyperuricemia.26-28 The two acute components that were independently associated with hyperuricemia on admission were WBC, which may reflect the inflammatory state of the patients, and BUN, which may reflect the hydration state. Therefore, it seems that the UA level reflects both baseline comorbidity and the acute state of the patient.
Hyperuricemia, together with leukocytosis, lymphopenia, and CRP level, were associated with mortality. Patients with hyperuricemia on admission had 3 times greater risk for death during hospitalization. However, in multivariate analysis, the independent predictors for mortality were older age, male sex, IHD, leukocytosis, high CRP, and impaired physical and mental condition (measured by the NSS). Based on these data and the independent association between UA level and leukocytosis, it seems that the association between UA level and mortality is partly due to the relationship between leukocytosis and mortality. Therefore, we suggest that hyperuricemia is a marker of a severe inflammatory response as expressed by leukocytosis. This assumption is supported by a previous study that showed an independent association between leukocytosis and mortality in patients hospitalized for COVID-19.29
Similarly, recent research by Chauhan et al.30 has shown an association between high serum uric acid levels and in-hospital mortality among COVID-19 patients. However, these findings are different from several studies conducted in China, which showed an association between short-term mortality and a lower UA level. We suggest that different racial and environmental factors may underlie this reverse correlation.
Hyperuricemia was more common among patients with severe-critical disease; however, in multivariate analysis it was not a predictor of these outcomes. We suggest that the UA level may reflect known association between morbid obesity and COVID-19 severity.
The functional and cognitive status of the patients, measured by the NSS, was the strongest predictor for mortality in patients with COVID-19. This finding is reasonable and well-matched to previous data regarding NSS as a predictor for adverse outcomes in hospitalized patients.31-33 Interestingly, patients with hyperuricemia had a higher mean NSS (18.6 vs. 15.1, P < 0.5). This finding, together with the higher NSS among patients > 70 years old with overweight (15.3, compared with 11.75 for patients without overweight), suggest that, paradoxically, in older adults, overweight and hyperuricemia may reflect less frailty and a better prognosis. Hence, UA–morbid obesity was not found to be an independent predictor among the total study population.
CRP was an independent risk factor for all adverse outcomes except mortality, which was predicted independently by leukocytosis. It is possible that when leukocytosis appears in patients with COVID-19 (it is not a common finding in this patient group), it reflects a severe inflammatory manifestation of the disease with high risk for mortality. Therefore, leukocytosis would be a stronger predictor of mortality than CRP level. This theory is supported by the low rate of leukocytosis among the total study population (15%) and a significantly higher leukocytosis rate of 48.4% among patients who died versus 9.3% among those who survived (P < 0.05).
The main limitations of this study are the relatively small sample size, the retrospective nature, and the unavailability of UA levels in 80% of patients admitted with COVID-19, which would introduce a confounding factor to the final data set. In addition, the blood samples were not drawn at precisely the same time after admission for all patients, which may affect the accuracy and reliability of the findings.
In summary, we found that hyperuricemia is associated with mortality and other adverse outcomes in patients hospitalized for COVID-19, but did not interdependently predict them. We suggest looking at hyperuricemia as a marker that integrates and reflects both poor prognostic baseline characteristics and acute components such as inflammatory state, hypovolemic state, and renal failure.
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