The key finding of this study is that urine cadmium had the greatest predictive value for disease severity among all studied clinical variables in the patients with COVID-19 who had no recent or chronic history of exposure to cadmium. In addition, the patients with severe COVID-19 in higher urine cadmium quartiles had significantly higher 60-, 90-day, and all-cause hospital mortality rates. Our findings suggest that urine cadmium at the diagnosis of acute SARS-CoV-2 infection could be a valuable early marker to predict the severity and clinical outcomes of patients with COVID-19.
Oxidative stress plays a crucial role in the pathophysiology of SARS-CoV-2 infection. Endothelial oxidative stress causes a reduction in vascular nitric oxide bioavailability, and this effect is proportional to the severity of COVID-19 and may participate in the pathogenesis of microvascular endothelial damage, cytokine storm, immunothrombosis, microangiopathy, and multi-organ injury during SARS-CoV-2 infection [16–18]. Cadmium exposure has been reported to alter reduction-oxidation (i.e., redox) balance and subsequently induce ROS overproduction, trigger oxidative stress and mitochondrial electron transport chain dysfunction, stimulate endoplasmic reticulum stress signaling pathways with ensuing apoptotic cell death, and thereby alter inflammatory responses and inhibit immune function [5, 11, 13–15, 22].
The potential impact and correlation of cadmium with disease severity and clinical outcomes of COVID-19 have not been clearly elucidated. In the current study, we found that the severe COVID-19 group had significantly higher values of blood and urine cadmium, significantly higher neutrophil/lymphocyte ratio, significantly higher values of inflammatory markers including ferritin, LDH, CRP and IL-6, and higher rate of oxygen support than the non-severe COVID-19 group. These findings suggest that cadmium exposure may worsen or aggravate the harmful effects of oxidative stress and dysregulated inflammatory or immune responses induced by SARS-CoV-2 infection, thereby further contributing to increased inflammation, impaired gas exchange, defective cell and tissue damage, and pulmonary and systemic organ injury, and consequently the severity of COVID-19.
Among the severe COVID-19 patients, those in the higher urinary cadmium quartiles had a significantly higher neutrophil/lymphocyte ratio, higher levels of inflammatory markers including ferritin, LDH, IL-6 and CRP, significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), and significantly higher risk of hypoxemia (i.e., lower PaO2/FiO2) requiring a significantly higher rate of invasive mechanical ventilation. In addition, the severe COVID-19 patients in the higher urine cadmium quartiles had worse clinical outcomes, including a significantly higher risk of shock status requiring the use of inotropic agents, significantly higher risk of ARDS, and significantly higher 60-day, 90-day, and all-cause hospital mortality rates (all p < 0.05). These findings suggest that a higher urine cadmium concentration, representing a higher total body burden of cadmium, may increase oxidative stress, promote excessive inflammation and immune responses, augment cytokine production, impair oxygen exchange, and cause distant organ damage. This may then predispose COVID-19 patients to serious complications, worse clinical outcomes and even death.
Long-term or chronic exposure to cadmium, even at lower levels, is carcinogenic to humans and can damage multiple systems, especially the kidneys, bones, and lungs. Long-term cadmium accumulation primarily occurs in the kidneys [8]. The half-life of blood cadmium is between 75 and 128 days, while the average half-life of cadmium in the kidneys ranges from 6 to 38 years [8, 9, 12]. Therefore, urinary cadmium value is a better surrogate of lifetime accumulation or long periods of exposure, total body burden and renal accumulation of cadmium, whereas the blood concentration of cadmium reflects acute or recent exposure [8, 9, 23].
The upper limit threshold for the value of urinary cadmium is lacking for many clinical diseases, including COVID-19 [8, 24]. The Food and Agriculture Organization and World Health Organization established a urinary cadmium threshold of 5.24 µg/g creatinine. However, some cohort studies have reported that a urinary cadmium threshold value below 5.24 µg/g creatinine was associated with adverse health effects such as an increased risk of type 2 diabetes, cardiovascular disease, chronic kidney disease and cancer, and that this threshold limit should be reassessed [7, 8, 25]. In the current study, the risks of severe COVID-19 and all-cause hospital mortality demonstrated stepwise increasing trends with an increase in urine cadmium/creatinine value. In multivariate regression models, urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.629, p = 0.043), and a value > 2.05 µg/g had the highest predictive value among all studied clinical variables (adjusted OR 5.391, [95% CI 1.127–25.794], p = 0.035), indicating that individuals with a higher urine cadmium concentration, reflecting higher total body burden or long-term exposure to cadmium, may be more vulnerable to severe COVID-19 and subsequently poor clinical outcomes and higher in-hospital mortality.
Our findings indicate that specific attention should be paid to individuals with risk factors to prevent serious complications of COVID-19. Previous studies have reported that lymphopenia, thrombocytopenia, and elevated values of LDH and CRP were all associated with increased severity and mortality in COVID-19 patients [3, 4, 26–28]. Hematological changes such as lymphopenia and thrombocytopenia are not rare and have been reported in up to 80% and 40% of patients with COVID-19, respectively. SARS-CoV-2 may directly infect lymphocytes, destroy lymphatic organs, and cause T cell exhaustion. Inflammatory cytokine-induced lymphocyte apoptosis and suppression of lymphocyte proliferation due to coexisting metabolic disorders (i.e., lactic acidosis) have also been associated with lymphopenia in patients with COVID-19 [26, 29]. The possible mechanisms of SARS-CoV-2 infection-induced thrombocytopenia include direct hematopoietic stem or progenitor cell invasion and lung injury mediated by autoantibodies and immune complexes, defective bone marrow microenvironment, decreased thrombopoietin production, and inhibition of megakaryocytopoiesis by cellular immunity and cytokine storm [30, 31]. Markedly higher levels of inflammatory indicators such as LDH and CRP have been reported in patients with severe COVID-19 compared to those with non-severe COVID-19, and this has been associated with higher risks of ARDS, ICU admission, and death [3, 26, 28, 32], similar to the results of our study. In the current study, besides urine cadmium, we found that lymphopenia, thrombocytopenia, elevated LDH, and elevated CRP were all independently associated with severe COVID-19 in the multivariate regression models (all p < 0.05). This finding suggests that excessive inflammation and immune suppression upon sepsis caused by SARS-CoV-2 infection may influence the severity and clinical outcomes of COVID-19.
There are several limitations to this study. First, although this cohort study was conducted at two medical centers in Taiwan, it may not be generalizable to other institutions. Second, the vaccination status was not completely recorded and SARS-CoV-2 variants were not checked in all individuals, although the omicron variant was predominant during the study period. Third, although cadmium concentration in a single spot urine specimen has been reported to be an indicator of long-term exposure to cadmium [10], we only collected blood and urine samples once at the diagnosis of acute SARS-CoV-2 infection, and so serial changes or dynamic monitoring of cadmium values was not possible. Finally, our objective in this observational study was to identify associations between blood or urine cadmium and clinical outcomes of COVID-19 patients without considering issues pertaining to causality. We did not examine the biological effect of cadmium on the pathophysiology of SARS-CoV-2 infection, and the exact cellular mechanism is still unclear.