Our results indicate that HCWs with severe symptoms may have shown a better immune response to SARS-CoV-2 infection. Inflammation caused by severe symptoms such as fever, chills, dry cough or shortness of breath, fatigue, and weakness causes a decrease and increase of Se and Cu, respectively, resulting in an imbalance in serum Cu/Se levels. Interestingly, decreased Cu/Se ratios in non-responders to SARS-CoV-2 infection indicate mild inflammation and weak immune responses. Therefore, Cu/Se ratio could represent an inflammatory and immune status in SARS-CoV-2-infected HCWs.
Despite the normal levels of Se in all HCWs, the Se serum levels in patients with severe symptoms were found to be lower than in patients with mild symptoms. In complication status such as COVID-19 disease, the severe symptoms indicate inflammation and involvement of the immune system in the body. Inflammation, pro-inflammatory cytokines, hypoxia, and many stress signals can affect the Se serum level, which led to aggravating and accelerating Se decline [21, 22]. The COVID-19 infection is characterized by systemic inflammation especially in the lung, which resulting hypoxia [1]. In a recent study by Sun et al., reduced Se status was reported in patients with systemic sclerosis, as an autoimmune disease with systemic inflammation, vasculopathy, fibrosis, and hypoxia [23]. Also, in another study by Younesian et al., for assessment of Se serum levels in COVID-19 patients with severe and mild symptoms, it was shown that patients with severe conditions had lower Se serum levels compared with patients with mild symptoms [10]. It seems that a decline in Se serum level is occurred in an inflammatory condition and considered as a negative phase reactant in these situations [24, 25].
In the current study, increased Cu serum level was also shown in HCWs with severe symptoms, such that some individuals had higher Cu serum levels versus normal range (up to 169.1 µg/dL). Unlike selenium, studies were shows that Cu is increased in infections, such that progressed rising in Cu serum level is the hallmark of infections [26, 27]. In another hand, the inflammatory conditions significantly affect Cu serum level, such that increased Cu is known as a positive phase reactant [28, 29]. Since the pathophysiology of SARS-CoV-2 is characterized by systemic inflammation, so the elevated Cu serum level in patients with severe symptoms is reasonable. In two studies by Bagher Pour et al., and Skalny et al., for estimate association of trace elements with severity and clinical outcomes of COVID-19 patients, it was shown that high Cu serum level is associated with severe symptoms, hospitalization, and mortality [16, 30].
Our results also indicated that HCWs with severe symptoms had a high Cu/Se ratio compared with mild symptoms subjects. Normal levels of trace elements cause maintain general health, but the imbalance between them could have serious consequences. Some trace elements are antagonists, which means they may compete against each other. In this regard, the association of Cu and Zn balance with inflammation is well known. Several studies have shown a correlation of high Cu/Zn ratio with an inflammatory condition such as oxidative stress [14], autoimmune diseases [31], infections such as SARS-CoV-2 [16], and cancers [17, 18]. In another hand, a low Cu/Zn ratio is associated with an increased risk of incident infections [32]. In terms of Cu and Se balance, Cu has also been shown to be a Se antagonist [33]. Thus, elevated Cu levels in inflammatory conditions can affect Se and lead to an imbalance in the Cu/Se ratio. The high Cu/Se ratio has also been reported in inflammatory conditions such as recurrent aphthous stomatitis [19], pulmonary arterial hypertension in systemic sclerosis patients [23], acute ischemic stroke [34]. So, it seems that a high Cu/Se ratio may be considered as an inflammatory situation such as SARS-CoV-2 infection.
Our results also demonstrate that HCWs with an IgG response to SARS-CoV-2 belonged to the group with severe symptoms. Positive and negative correlations were found between Cu and IgG responders, and Se and IgG non-responders. Also, the Cu/Se ratio was higher in IgG responders compared with IgG non-responder subjects. The inflammation during infections such as SARS-CoV-2 is caused by the strong activation of the innate immune system. SARS-CoV-2 activates innate immune cells, which led to the production and release of pro-inflammatory and inflammatory cytokines named cytokine storm. Although cytokine storm leads to severe symptoms, hospitalization, and mortality in patients with COVID-19, it can also activate the efficient adaptive immune responses [35, 36]. The link between innate and adaptive immunity is well known, and numerous studies have indicated strong an innate response lead to the full activation of adaptive immunity [37]. In a study by Hackler et al., it was reported that surviving COVID-19 patients showed higher Cu and Se serum levels in comparison to COVID-19-dead patients, and Cu and Se serum levels are contributed to a good prediction of survival [38]. It seems that the Cu/Se ratio could be considered as the status of immune response activation and survival in patients with COVID-19 disease.
The limitation of the current study was the small population, and authors suggest this finding estimate in a large population with severe symptoms and strong immune response against SARS-CoV-2 infection. As well as, we measured only anti-SARS-CoV-2 IgG, so other antibodies, such as long-term IgM and IgA, may be involved in the long-term immune response to COVID-19 and protect HCWs against re-infection. In another hand, we did not estimate cellular immunity in this matter, and individuals with severe symptoms, and without humoral response, may have efficient cellular immunity against infection, and further research is needed.