From
in vitro and some clinical studies, it is well known that zinc elicits activity against several viruses
[14]. Indeed, it was demonstrated that zinc inhibits the activity of RNA dependent RNA polymerase (RdRp) of Hepatitis E virus
[15]. It was further shown
in vitro that zinc inhibited coronavirus RdRp activity and that zinc ionophores blocked coronavirus replication
[16]. Despite the well-known antiviral effects of zinc and possible properties of CQ/HCQ as zinc ionophore, the combination of zinc with one of these established drugs to achieve additive or even synergistic antiviral effects ought to be still confirmed.
Zinc is a general stimulant of antiviral immunity
[14]. In the context of COVID-19 morbidity and mortality, zinc deficiency may be relevant for the outcome of patient populations with severe clinical courses of COVID-19 including elderly patients, patients with hypertension, diabetes, coronary heart disease, or chronic obstructive lung disease. In addition, hypertensive and cardiovascular disease patients are frequently treated with hydrochlorothiazide, angiotensin-converting-enzyme inhibitors, and angiotensin 2 receptor antagonists which can result in an increased urinary excretion of zinc with subsequent systemic zinc deficiency
[17]. Zinc deficiency was also demonstrated in diabetic patients
[18]. Decreased zinc plasma levels are even present in a large number of healthy elderly patients
[19]. The NHANES III study demonstrated that 35%–45% of adults aged 60 years or older had zinc intakes below the estimated average requirement of 6
.8 mg/day for elderly females and 9
.4 mg/day for elderly males. 20%–25% of older adults still had inadequate zinc intakes even when intakes from both food and dietary supplements were considered
[20]. It may be speculated that also younger adults or even infants and adolescents with present zinc deficiency could be at higher risk for severe courses of SARS-CoV-2 infections. Therefore, we hypothesize that effective zinc supplementation during treatment of COVID-19 with CQ and HCQ, which have zinc ionophore characteristics, may result in increased intracellular zinc levels in general and in lysosomes specifically. Higher intracellular zinc levels might result in a more efficient RdRp inhibition and consequently a more effective inhibition of intracellular SARS-CoV-2 replication, potentially improving clinical outcomes of COVID-19 patients treated with CQ or HCQ. Whether this accumulation and treatment effect may sufficiently occur in relevant pulmonary tissue of COVID-19 patients has to be confirmed.