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Zinc is a trace element that plays a role in the development and function of the immune system exhibiting direct or indirect anti-viral properties [13, 14]. High intracellular zinc levels were reported to stall the replication of coronavirus (SARS-CoV-2) and influenza virus that caused the severe acute respiratory syndrome [14,15,16]. Some reports demonstrate the synergistic effect of zinc with anti-viral therapy in SARS-CoV-2 . The benefit of zinc supplementation on the immune system function has been previously observed in non-COVID-19 patients [17, 18]. However, there is inadequate evidence to support the use of zinc for COVID-19 treatment in critically ill patients [19, 20]. Yet, providers continue to use it as adjunctive therapy in this patient population. Therefore, we aim to evaluate the efficacy and safety of zinc supplementation as adjunctive therapy in treating critically ill patients with COVID-19.
This study aimed to evaluate the efficacy and safety of zinc sulfate as adjunctive therapy in critically ill patients with COVID-19. The primary endpoint was the 30-day mortality in critically ill patients who received zinc sulfate as adjunctive therapy. The secondary endpoint included the in-hospital mortality, ICU length of stay (LOS), hospital LOS, ventilator free days (VFDs), and evaluation of complications during ICU stay after zinc initiation, including acute kidney injury (AKI), liver injury, and thrombosis/infraction during ICU stay.
The pre-admission nutritional status is an important indicator for disease severity and might impact the COVID-19 patient's survival. A higher risk of mortality and longer stay in hospital was reported in critically ill COVID-19 patients with higher Nutritional Risk Screening (NRS) 2002 . We assessed our patients' nutritional status using the NUTRIC score, which was not significantly different among the groups after propensity score matching. It worth to mention, that Saudi population has a low intake of some micronutrients (such as zinc and selenium) which might have an impact on the preadmission nutritional status and the disease progression . In agreement with our explanation, a recent study has evaluated the impact of preadmission zinc levels in non-critically ill COVID-19 patients and showed that patients with hypozincemia have a higher hospitalization rate due to respiratory complications within ten days . Thus, the impact of hypozincemia on the disease progression and the clinical outcomes still worth further investigation in critically ill COVID-19 patients.
Several reports showed that elevated inflammatory surrogate markers such as d-dimer and fibrinogen levels had been linked with a higher mortality rate in critically ill COVID-19 patients [4, 28, 30]. Zinc effect on COVID-19 surrogate markers was not well studied. In our study, patients who received zinc supplementation had lower follow-up d-dimer and fibrinogen levels during their stay. This may play a role in COVID-19 disease progression, which might be translated to the mortality benefit seen in our study.
Currently, the available evidence about the use of zinc in critically ill COVID-19 patients is limited. Many of the previous reports investigated zinc use in either non-COVID-19 or non-critically ill patients. As we are writing this manuscript, there is an ongoing double-blinded RCT study investigating the use of high-dose zinc in critically ill patients with SARS-COV2 . Compared to the published data, our study is one of the few studies that assessed the use of zinc in critically ill patients with COVID-19 with a propensity-score-matched group of patients. 2b1af7f3a8