Course and Survival of COVID-19 Patients with Comorbidities about the Trace Element Status at Hospital Admission
Selenium (Se) and zinc (Zn) are essential trace elements needed for appropriate immune system responses, cell signaling, and anti-viral defense. A cross-sectional observational study was conducted at two hospitals in Ghent, Belgium, to investigate whether Se and/or Zn deficiency upon hospital admission correlates to disease severity and mortality risk in COVID-19 patients with or without co-morbidities. Trace element concentrations along with additional biomarkers were determined in serum or plasma and associated with disease severity and outcome. An insufficient Se and/or Zn status upon hospital admission was associated with a higher mortality rate and a more severe disease course in the entire study group, especially in the senior population. In comparison to healthy European adults, the patients displayed strongly depressed total Se (mean ± SD: 59.2 ± 20.6 vs. 84.4 ± 23.4 µg L−1) and SELENOP (mean ± SD: 2.2 ± 1.9 vs. 4.3 ± 1.0 mg L−1) concentrations at hospital admission. Particularly strong associations were observed for death risk of cancer, diabetes, and chronic cardiac disease patients with low Se status, and of diabetes and obese patients with Zn deficiency. A composite biomarker based on serum or plasma Se, SELENOP, and Zn at hospital admission proved to be a reliable tool to predict severe COVID-19 course and death or mild disease course. We conclude that trace element assessment at hospital admission may contribute to a better stratification of patients with COVID-19 and other similar infectious diseases, support clinical care, therapeutic interventions, and adjuvant supplementation needs, and may prove of particular relevance for patients with relevant comorbidities.
The infectious coronavirus disease (COVID-19) caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) constitutes a life-threatening condition, in particular for a subgroup of patients with underlying comorbidities. Besides age , the most relevant risk factors for severe COVID-19 course and SARS-CoV-2 infection-associated death include hypertension, cancer, respiratory disease, obesity, and diabetes mellitus [2,3]. These conditions are associated with metabolic dysregulation and inflammation , compromised signaling by reactive oxygen species (ROS) , and may involve a disturbing trace element status [6,7]. Among the important, intensively regulated and immune-relevant micronutrients are the essential trace elements copper (Cu), selenium (Se), and zinc (Zn) . All three micronutrients are implicated in acute inflammation and in the concept of health-supporting nutrition to counteract ongoing inflammation, i.e., the natural progressive age-dependent subclinical inflammatory processes finally causing organ dysfunction and degenerative diseases . Accordingly, micronutrients may be of high relevance for reducing SARS-CoV-2 infection risk, supporting the immune system in combating the virus, and avoiding long-term adverse health issues from COVID-19 [10,11,12,13,14].
The micronutrient Se is needed for the biosynthesis of enzymatically active selenoproteins, including members of the families of glutathione peroxidases (GPX), thioredoxin reductases, or iodothyronine deiodinases . Given their crucial roles in regulating reactive oxygen species (ROS) levels, energy metabolism, and overall redox status in nearly all mammalian cells, Se status is closely interrelated with inflammation and immune responses . Se deficiency has been associated with viral and bacterial infections, both in model systems and clinical studies [17,18]. The spread and mutation rate of influenza and Coxsackie virus were highly elevated in Se-deficient animals [19,20,21]. Accordingly, Coxsackie virus infection causing Keshan disease, i.e., severe congestive cardiomyopathy, develops endemically in Se-deficient populations . The biologically meaningful threshold currently used to define Se deficiency and sufficiency, respectively, has been based on the occurrence and prevention of this endemic infectious disease , or the full expression of selenoproteins . The strong interrelations between virus biology and infections, nutrition, and human health are supported by recent analyses of patients with COVID-19, where a positive association of cure rate with regional Se status was observed in China , along with an increased mortality risk by Se deficiency in European patients .
There are also several studies and reviews highlighting a potentially important role of Zn supply, Zn status, and Zn distribution in COVID-19, suggesting supplemental Zn as a promising therapeutic adjuvant . Virus replication is enhanced in Zn deficiency, and supplemental Zn can inhibit virus spread and proliferation, as shown in preclinical studies and infected subjects [26,27,28]. It is assumed that Zn deficiency predisposes to severe COVID-19 , and accordingly, high death rates of COVID-19 patients with Zn deficits have been observed in clinics [30,31].
As Belgium has been heavily affected by COVID-19, we studied the trace element status of a set of consecutive patients admitted to two hospitals in the city of Ghent. We investigated the possible interrelationship between COVID-19 severity and mortality risk with the trace element status and the prevalent comorbidities diabetes mellitus, obesity, chronic cardiac disease, and cancer.2. Materials and Methods
Study Design and Participants
A cross-sectional study of patients with COVID-19 was conducted at Ghent University Hospital (UZ Gent) and AZ Jan Palfijn Hospital in Ghent (JPH Ghent), Belgium. The study was conducted by the Declaration of Helsinki. Ethical counseling was provided by the local Ethics Committee of JPH Ghent and UZ Gent, and approval was granted (BC-07492). All patients enrolled or next of kin provided written informed consent.
Total trace elements (Se, Zn, Fe, and Cu) along with GPX3 activity and selenoprotein P (SELENOP) levels were determined from serum (JPH Ghent) or plasma (UZ Gent) of the patients, essentially as described . The group of patients consisted of subjects with proven SARS-CoV-2 infection. The observational study was conducted over a predefined period with slightly different study protocols at the two study sites, i.e., UZ Gent (study 1) and JPH Ghent (study 2). The inclusion criteria comprised adult age (18–100 years) and a positive COVID-19 diagnosis, as based on detection of SARS-CoV-2 viral RNA using routine RT-PCR analysis as described . The full study cohort consisted of n = 138 patients, 79 of whom enrolled in study 1 and 59 into study 2. Five patients from study 1 were transferred to another facility during the study, and one patient was still hospitalized at the end of the study period. These patients were excluded from the clinical analyses. About half of the COVID patients (52%) participating in both studies were aged above 65 years, the usual retirement age in Belgium, and 17% were above 80 years old. Information on age, COVID-19 diagnosis, and sex were available for both study 1 and study 2. Data on potential risk factors for severe COVID-19, such as information on diabetes mellitus, malignant neoplasm, obesity, and chronic cardiac disease, were available in the database of study 1 only. This information along with age, gender distribution, and BMI are presented in Table 1.
Trace Element Status at Hospital Admission
All of the patients of study 1 were analyzed at hospital admission (T1); Cu, Fe, and Zn status were determined as total element concentrations in plasma, whereas Se status was assessed by three interrelated biomarkers, i.e., total Se concentration, SELENOP levels, and GPX3 activities. The data are separated into subgroups of male and female patients, patients above and below 65 years old, and patients with or without malignant neoplasm, diabetes, chronic cardiac disease, and obesity, respectively. The results indicate that Cu levels were adequate in the majority of samples. Fe levels were higher in male patients, whereas Cu levels were higher in female patients. Plasma GPX3 activities were higher in patients below 65 years old. The trace element concentrations were not significantly different about diabetes, chronic cardiac disease, or obesity, but tumor patients presented with significant deficits in Zn and SELENOP (Table 2). Out of the 10 subjects with the lowest plasma Zn levels among the entire cohort, seven were from the small group of cancer patients. Three of the five patients with the lowest blood Fe concentrations died during the study; these non-survivors also displayed profound simultaneous Se and Zn deficits and were thus exhibiting a kind of universal trace element-deficiency.
Infections with SARS-CoV-2 cause mild or severe COVID-19 course, and predictive markers for better stratification of patients at hospital admission, are needed. In this study, we report on particularly low total Se, total Zn, and depressed SELENOP concentrations in the majority of patients who were hospitalized with proven COVID-19 infection at one of two hospital sites in Ghent, Belgium. The analysis of patients with comorbidities highlighted a particularly pronounced deficit of plasma Se, Zn, Fe, and SELENOP in cancer patients, along with a strong positive interrelation of preserved Se status with high survival chances under these conditions. Similarly, disease severity and length of hospital stay were associated with Se and SELENOP deficits and were already detectable at admission. The focused analysis of trace elements at admission about mortality rate highlighted Zn deficiency as a particular relevant risk factor for patients with diabetes mellitus. The majority of non-survivors were characterized by a combined Se and Zn deficit, and both trace elements recovered in blood during the hospital stay and towards discharge as indicators of high survival chances.
The findings are in general agreement with prior reports on trace elements in COVID-19, and their interrelation with mortality risk. A seminal publication from China indicated higher cure rates from COVID-19 in areas with better habitual Se status . This interrelation was also observed for individual patients, where low and declining Se concentrations in blood were associated with poor survival odds . Notably, an increased mortality risk with Se deficiency was not restricted to the elderly population but also observed in relatively young and otherwise healthy patients without known comorbidities in a respective study conducted in India . The depressed Se status is likely caused directly by the viral infection, as the concentrations observed in patients with COVID-19 are far below reference ranges and are recovering towards normal values in the majority of survivors. In terms of how far low Se predisposes to infection, severe disease course and hospitalization are currently unknown, as the samples analyzed at hospital admission are not representative of the full population of infected subjects. Still, a compromised immune response to SARS-CoV-2 infection and suppressed immune cell activity under Se deficiency can be assumed and would be in line with preclinical studies and circumstantial evidence from other infections [37,38]. The negative acute phase response of serum SELENOP and Se might close a vicious cycle of declining Se status with ongoing inflammation unless counteracted by anti-inflammatory medication, successful immune response, or sufficiently high Se supply after infection and during hospital stay [18,39,40,41,42]. The interrelationship of viral or bacterial infection, activated immune response, and declining Se status does not constitute a unique characteristic of COVID-19, but was similarly observed before in other diseases, like sepsis, HIV, influenza, or coxsackievirus infection [20,43,44,45,46]. Similarly, an association of low Se status with high mortality risk is a common finding in studies with severely diseased patients, in particular with patients requiring support on the intensive care units [43,44,47].
Besides Se, Zn constitutes the second most relevant trace element for immune cells, inflammation, and for combating SARS-CoV-2 infections [13,48,49]. Deficiency in Zn has been described as a risk factor for mortality in COVID-19, and plasma Zn concentrations at admission were associated with 21% and 5% mortality, respectively, about a plasma Zn threshold of 500 μg L−1 . Accordingly, no loss to COVID-19 was observed in an independent clinical study, when the patients displayed a replete Zn status of ≥800 μg L−1 at hospital admission, in contrast to an 18.5% mortality rate below this threshold . However, low Zn status seems to recover relatively fast after hospitalization, as reported before , and as observed in the current study (Figure 3F). The transient decline may reflect a dynamic redistribution between blood and immune cells.
Given the strongly elevated mortality observed in the group of patients with Se concentrations at hospital admission below 55.2 µg L-1, the current threshold for defining deficiency (>0.25 µM, equal to serum or plasma Se of 20 µg L−1), which was based on the prevention of cardiomyopathy upon infection by the Coxsackie virus, should be reconsidered . Besides COVID-19 mortality, low Se status predisposes to several diseases, including cancer, cardiovascular disease, or autoimmune thyroid disease . Together with the growing body of evidence linking Se deficit to increased mortality risk in COVID-19, it appears timely to raise the threshold and consider supportive nutrition in hospitals and ideally avoid such low supply in the general population, as has successfully been done in Finland for more than three decades . A cross-European analysis of COVID-19 mortality rates in the different countries about their habitual Se intake and blood Se status would be most suitable to test this notion and consider appropriate preventive measures.
The mortality in our study was elevated in Se and Zn deficiency, in particular within the groups of obese, chronic cardiac disease, cancer, and diabetes patients. These conditions confer an increased mortality risk in COVID-19 and are often associated with (sub-)clinical inflammation, again potentially closing a vicious self-amplifying cycle [54,55]. As cancer and chronic cardiac disease were associated with higher mortality particularly in the Se-deficient patients, obesity was associated with higher mortality in Zn-deficient patients, and both Se- and Zn-deficiency conferred increased mortality risk in particular for diabetes patients, it is hypothesized that Se and Zn deficiency may aggravate the negative impact of cancer, obesity, chronic cardiac disease and diabetes on an adequate immune response in COVID-19.
Both the Se and Zn status, in particular SELENOP, tended to improve during recovery. Furthermore, the younger patients who had to go through a critical disease course or even lost their lives during the hospital stay often exhibited pronounced Se deficiencies at admission, which were even more severe compared to older patients going through a similar disease severity. From these observations, together with the relationship between low Se status, disease severity, and mortality risk, we hypothesize that a sufficiently high Se status is the most critical factor for COVID-19 course in young subjects, and in patients with comorbidities. To translate these findings into a useful diagnostic scheme for assessing and predicting COVID-19 course at hospital admission, the following scheme has been developed and will be tested in follow-up studies:
Our data confirm that an insufficient Se (total Se and SELENOP) and Zn status at admission to the hospital is associated with exceptionally high mortality risk and severe disease course with COVID-19. Our study contributes to the set of informative biomarkers in COVID-19, with potential relevance also to other similar infectious diseases. Given the predictive accuracy of Se and Zn deficiency as a mortality risk factors at hospital admission, supplemental Se and Zn supply should be considered to support the immune system, in particular for patients with inflammation-related comorbidities like cancer or diabetes mellitus. However, causality remains unknown due to the observational nature of this study. Randomized clinical trials are needed to test whether Zn and Se supplementation to patients with diagnosed deficiencies are relevant for reducing mortality risk, decreasing hospitalization time, accelerating recovery, and potentially even preventing post-COVID-19 syndrome. From our point of view, there are no obvious reasons against such supportive adjuvant measures, as long as clinically recommended dosages are not surpassed. Credited to G. Du Laing
(Laboratory of Analytical Chemistry and Applied Ecochemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Gent, Belgium)