7. Zinc

7.1. Metabolism and Functions, Recommended Daily Allowances
Zinc is an essential trace element for humans, required for the function of numerous enzymes and transcription factors. It plays a key role in regulating the function of both the adaptive and the innate immune system [14,228,229]. Dietary sources of zinc are animal products such as meat, fish, eggs, and dairy, but it is also contained in whole grains, nuts, and legumes. Zinc from animal sources has higher bioavailability compared to zinc derived from plant products. Non-digestible plant ligands such as phytate, some dietary fibers, and lignin chelate zinc and inhibit its absorption.
Zinc is absorbed throughout the digestive tract through specific transporters, such as ZIP4 (SLC39A4), whose mutation is responsible for the rare, lethal autosomal-recessive inherited acrodermatitis enteropathica.
Zinc deficiency is estimated to affect billions of people worldwide, especially the elderly and children in developing countries, pregnant women, vegan, and vegetarians. Zinc is considered deficient if plasmatic levels are below 60 mcg/dL. In Italy, the recommended daily allowance for zinc is 3 mg/day for infants below 12 months of age, then it raises gradually to a recommended intake of 9–12 mg/day for adolescents and adults [230].
Zinc’s effect on the immune system is complex; it can both enhance and inhibit different immune functions to reach a correct balance between pro and anti-inflammatory effects through various mechanisms. A correct intake of zinc is essential to limit the overproduction of inflammatory cytokines: in vitro and human studies show that zinc deficiency is associated with an increased inflammatory response and excessive release of pro inflammatory cytokines such as IL-2, IL-6, and TNF-alfa, regulated through the NF-κB signaling pathway [230,231,232,233,234,235,236,237]. Zinc also enhances the number of inducible regulatory T cells [238,239,240,241]. Another important role played by zinc is the maintenance of membrane barrier integrity, which is essential in the pulmonary and intestinal epithelia that constitute the first barrier to protect the organism from pathogens. [242,243,244]. Zinc supplementation is also effective in decreasing oxidative stress [245,246], in shortening the duration of cold symptoms in adults [247], and was found to have a direct antiviral effect on RSV [248], Dengue virus [249], and coronaviruses [250]. Lastly, some authors suggested that a combination of chloroquine with zinc might enhance chloroquine’s toxicity on viruses [249,250,251,252]. Te Velthius et al. [249] reported that the combination of Zn2+ and zinc-ionophores like pyrithione can increase the intracellular Zn2+ concentration, and thus inhibits the replication of SARS-coronavirus (SARS-CoV) and equine arteritis virus in cell culture.

7.2. Zinc Supplementation in Treating Viral Infections
Considering the known effects of zinc in regulating the immune system, trials have been conducted to investigate the efficacy of zinc in treating respiratory illnesses (Table 8) [253,254,255,256,257,258,259,260,261,262,263,264,265,266,267].
In a 2018 study, serum zinc levels were found to be significantly lower among pneumonia pediatric patients admitted to PICU compared with patients admitted to other wards; there was a statistically significant decrease in zinc level in critically ill children complicated by sepsis, mechanically ventilated and fatal cases [252]. Some studies reported similar duration of hospital stay, time to symptoms resolution, and risk of treatment failure in the intervention and in the control group [254,255,256,258,259,262,264,265], while others described partially positive results. Basnet and colleagues [260] found that zinc recepients recovered slightly faster than controls, although the difference was not statistically significant; Sempertegui et al. [263] evidenced that a higher basal zinc concentration was associated with faster resolution of chest indrawing, although there was no difference in time needed to fully recover nor in the risk of treatment failure; Mahalanbis et al. found a reduced duration of ALRI symptoms in boys, but not in girls [253].
Other trials evidenced instead positive results with zinc supplementation in acute respiratory infections: in 2011, Valavi et al. [257] described a faster resolution of symptoms in zinc-supplemented children; in 2012, a lower mortality rate was evidenced in Uganda in children who received zinc supplementation during the acute infection [261]; in 2019, Acevedo-Murillo and colleagues [266] reported a quicker improvement in the clinical status of pneumonia pediatric patients receiving zinc supplementation; in a Thailandese 2019 trial, zinc supplementation was associated with a shorter hospital stay and quicker resolution of symptoms [267].
Overall, the available data does not conclusively assert the efficacy of zinc in treating an existing acute lower respiratory illness in children, as also described in a 2012 meta-analysis from Das and colleagues [268]; more studies are needed to definitively establish if, and at what dose, zinc should be supplemented to children during an acute respiratory infection.

7.3. Zinc Supplementation in Preventing Viral Infections
From the early 2000s, various studies were conducted, mainly in children from lower socio-economic settings, to establish whether daily or weekly zinc supplementation could help in preventing respiratory tract infections (Table 9) [269,270,271,272,273,274,275,276,277,278,279,280,281].
Different studies reported a reduced incidence of respiratory infections in the zinc receiving group [269,271,272,273,280]. In 2007, Sazawal et al. reported a slight reduction in the relative risk of all-cause mortality in children supplemented with zinc in Zanzibar [277]. Other studies found instead that zinc supplementation had no significant effect on the frequency of respiratory infections [274,275,276,278,279,281]. Some of these trials used a lower daily dose of zinc, which might be one of the reasons why the supplementation was less effective; however, both negative and positive results were reported with different zinc dosages, from 5 up to 30 mg/day.
Overall, different reviews and meta-analysis confirmed the efficacy of zinc supplementation in preventing respiratory illnesses: Aggarwal et al. reported that zinc supplementation for more than 3 months significantly reduced the frequency and severity of diarrhea and respiratory illnesses [282]; in 2010, Roth et al. found that routine zinc supplementation reduced the incidence of childhood ALRI [283]; in 2011, Yakoob and colleagues described a reduction in diarrhea and pneumonia mortality in children from developing countries who received zinc supplementation for over 3 months [284]; a 2016 systematic review also reported a statistically significant lower incidence of pneumonia (−13%) in children receiving zinc supplementation [285].