The current COVID-19 pandemic caused by SARS-CoV-2 is reaching unexpected limits worldwide. In the first six months after the first flares were detected in China in December 2019, more than 10 million infections have officially been recorded—surely higher if real cases could be counted—with around 5% of fatal cases (between 1 and 13% recognized according to country), and the pandemic continues in crescendo (see the updated information in [1
]). Consequently, factors that can condition the proper functioning of the immune system are coming into the spotlight and will increase in the coming months, when new waves can be expected. As no specific treatment or vaccine against the disease is available yet, new knowledge of other possibilities to prevent and/or improve overall disease management of COVID-19 becomes more pressing. Complementary to drug treatments and vaccines, nutritional and lifestyle factors must be considered as factors that can enhance the immune system.
Bearing in mind the fact that our organism is in constant fight against infections through the immune system, its maintenance at an optimal level of functionality is a central objective more than ever, due to the current circumstances. Thus, the relevance of optimal nutritional status for immunity must become essential. Accordingly, there is increasing knowledge as to how food, nutritional habits, and some other lifestyle aspects are essential to keeping the immune system working properly [2
]. In this regard, the optimal nutritional status of some essential specific micronutrients, including vitamins and minerals, stands out above the rest of the nutrients (without playing other nutrients down) because of their contrasted potential beneficial health effects, even beyond the essential requirements classically considered in nutrition. According to the scientific information available, the competent scientific Panel of the European Food Safety Authority (EFSA) determined that the following six vitamins are important for the healthy maintenance of the immune system: D [3
], C [3
], A (and ß-carotene) [3
], and B-group vitamins (especially B6
, Folate, and B12
]. Consequently, the EFSA Panel concluded that there is definitive evidence of the cause–effect relationship between the daily intake of these vitamins and the normal, healthy functioning of our immune system. Meanwhile, a similar accreditation corresponds to four essential minerals: Zinc [6
], Copper [7
], iron [9
], and selenium [10
] are considered to be necessary for the optimal working of the immune system by the EFSA.
However, this does not mean that other nutrients, foods, or even commercial preparations with specific labelling attributing them health properties in the immune field are not also relevant, but they have not provided EFSA with sufficient scientific evidence to demonstrate this. In fact, many of the health claims that were on the market have been rejected. Consequently, and always staying within the context of balanced diets and a healthy lifestyle, it is convenient to ensure the optimal intake of these 10 micronutrients that are supported by very rigorous scientific evidence as having an essential role in the proper working of the immune system. Besides, some factors could interfere in the relationship between nutrient intake and actual nutritional status, including environmental factors, food-matrix components, and, above all, genetic features.
In this context, the main aims of this report focus on (1) identifying those nutrients scientifically supported to promote the optimal functioning of the immune system; (2) analyzing their nutritional status in European countries and studying their relationship with epidemiological COVID-19 indicators; and (3) describing genetic (and other) factors that compromise suboptimal nutritional status for the abovementioned specific nutrients. Therefore, nutritional (and nutrigenetic) features of 10 European countries (Spain, Belgium, Italy, the United Kingdom, Portugal, France, the Netherlands, Germany, Denmark, and Finland) were characterized from open databases and published studies, and contextualized within the current coronavirus pandemic framework. Thus, the relationship of identified nutritional parameters with epidemiological indicators of COVID-19 (incidence, mortality, and relative mortality) in the selected countries was analyzed.
The highest European authority in food safety, EFSA, endorsed the impact of the correct nutritional status of vitamins (D, A, C, Folate, B6 and B12) and minerals (zinc, iron, selenium and copper) on immune system health, so the scientific evidence of the beneficial effect of these micronutrients on immunity and protection against infective diseases is considered to be beyond doubt. In this report, an updated review of the specific effect of these 10 micronutrients on the immune system was carried out, focusing on the context of the COVID-19 pandemic.
Population intake levels of 10 of these specific nutrients and their compliance with country-by-country recommendations were analyzed and contrasted with epidemiological features of the SARS-CoV-2 pandemic. Observational data suggest that vitamin/mineral requirements are not fulfilled by diet in the EU and could be a limiting factor in the immune response to fight against infections.
The nutritional data analyzed, displayed in Table 2
, shows that Vitamin D intake is rather deficient in all the countries (to a different extent depending on the country), with Spain, France, and Italy as the countries with the lowest intake. This scenario is repeated in the case of Folate, but without reaching such low intake levels. Suboptimal iron intake is found in 6/10 of the countries analyzed; and Vitamin C and zinc in 5/10. On the other hand, Vitamin A intake levels are only suboptimal in Spain. None of the countries analyzed revealed intake below the recommendations with regard to Vitamin B12
. Despite the fact that selenium, copper, and Vitamin B6
data are missing for some countries, suboptimal consumption of selenium (6/7) and copper (5/7) can also be observed. In contrast, only two countries have intakes below the Vitamin B6
Although cross country comparison is limited by the heterogeneity of data collection protocols and dietary assessment methods, a number of previous dietary surveys have found widespread prevalence of suboptimal intakes for several micronutrients across the European region [151
], ranging from 11 to 30% for copper, Folate, selenium, Vitamin B12
, and Vitamin C [152
]; and four of the eight trace minerals (i.e., selenium, zinc, Iodine, and copper) show a high prevalence of insufficiency in the elderly, which is worsened by the requirement for institutional care [40
]. Thus, country specific genetic requirements have also been taken into account as a factor to more accurately point out the risk of suboptimal intake of the selected nutrients.
In this context, the European countries worst hit by the pandemic show population% with suboptimal intake of vitamins and minerals that are important to the immune system. Thus, incidence of infection by the new coronavirus and deaths caused by COVID-19 are associated with poor dietary intake of vitamins D, A, and B12
). In this scenario, Spain shows the worst data in relation to insufficient vitamin D and vitamin A intake, and is located among the top-3 of the worst vitamin B12
data (Figure 2
A), coinciding with the country with the highest incidence of COVID-19 and the second in mortality, at the time the data analysis was performed (Table 2
). In addition, Spaniards could display genetic features related to a higher risk of having lower circulating levels of Vitamins A and B12
, for which they are deficient, which might further compromise whispered deficiencies. In the same way, the next two countries with the highest incidence of COVID-19 (after Spain and Belgium), Italy and the UK, show deficiencies in the consumption of Vitamin D and, therefore, a higher genetic risk for its deficiency, which could also be related to the high percentage of deaths with respect to COVID-19 cases. Thus, needs of vitamin D coverage seem to play a key role in maintaining the immunity of individuals [46
], which would be reflected in the greater effect of the pandemic in countries with major deficiencies in its consumption. In this fashion, Vitamin D status must be monitored in well-characterized deficient populations to prevent COVID-19 incidence; and its supplementation ought to be considered, presumably in patients with deficient serum levels (i.e., levels < 10 ng/mL) in order to reduce disease morbidities and/or mortality rates [54
Besides, a lower population% with covered needs of vitamin C, iron, and copper is related to higher relative mortality rates from COVID-19 (Figure 3
). Accordingly, the UK presents a large population% with suboptimal intake for these three micronutrients; and, in addition, greater genetic risk of decreased levels of vitamin C.
Beyond the 10 essential nutrients with evidence supported by the EFSA on their role in the proper function of the immune system, there are other nutrients and bio-active compounds, the evidence of which is still scarce, but which could also boost immunity and must be considered.
In this regard, Polyunsaturated Fatty Acids (PUFA) are a bio-active group of compounds present in fish oils, algae, and other food sources [153
]. Despite the fact that genetic and anthropometric factors should be taken into account to consider their benefits, omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) show anti-inflammatory proprieties [154
] and a combined adequate intake of 250 mg/day is considered necessary for the maintenance of general cardiovascular health [156
]. In this context, the potential benefits (and risks) of omega-3 PUFA supplementation to COVID-19 patients were recently reviewed [157
]. The authors of this last paper concluded that more randomized, controlled trials are needed to evaluate the benefits of EPA and DHA supplementation because, even though EPA and DHA might improve inflammatory resolution and recovery of COVID-19 patients, it is also plausible that the excess of these compounds could promote non-enzymatic oxidation of cell membranes and cellular damage by increased pro-oxidative cell status [157
In addition, other essential vitamins and minerals beyond the 10 considered by the EFSA could be candidates to be considered for their role in the potential improvement of the immune system due to their antioxidant potential and as modulators of the activity of immune cells, namely Vitamin E [158
] and Magnesium [159
]. Moreover, other food rich bio-actives or bio-active compounds per se
have also been proposed either as potential enhancers of the immune system or as part of COVID-19 drug treatments. For instance, it is well documented that curcumin exerts health benefits on the immune system because of its positive effects on oxidative stress, microbiota, and antibacterial or antiviral action [160
]. Subsequently, this polyphenol has also been proposed recently as a potential treatment for this novel coronavirus disease, based on its hypothetical capacity to inhibit cell entry or virus encapsulation [160
] or on the indirect relationship with cardiovascular outcomes, ACE2 expression, and curcumin treatment observed in animal models [161
]. In the same way, the probable immunoenhancing effect of other promising phytonutrients must be considered as potential preventive nutritional treatments (or even in formula preparations), such as stilbenes [162
] or quercetin [163
]. Finally, it is imperative to keep watching out for the health of the microbiota by means of pre- and probiotics to boost the host’s immune system [164
]. Beyond specific nutrients or bioactive compounds, the potential impact on immunity of diets that cause an elevation of ketone bodies or their exogenous administration must also be assessed. According to the conclusions of a recent review, ketone bodies are endogenous metabolites involved in cellular energy homeostasis, but they also have important signaling activities that affect immunological activity. Therefore, knowledge regarding the role of ketone bodies in the fight against respiratory viral infections and the development of intervention studies based on the administration of exogenous ketone bodies as new immunometabolic therapies for these diseases could offer potential resources to deal with the SARS-CoV-2 pandemic [165
]. Finally, due to the continuous production of scientific evidence and the results of the first clinical trials, it cannot be ruled out that other compounds must also be considered as potential strengtheners of the immune system, and other elements beyond genetics must be taken into account as factors that require less bioavailability of these essential nutrients. Therefore, it is necessary to continuously review the state of the art of factors that may play a role in the prevention and fight against COVID-19.
It is important to mention that the approach analyzed here responds to an ecological study profile and the results obtained must be considered within the range of advantages and limitations of this type of approaches. On the one hand, ecological designs are frequently carried out to study the first suspicions of the negative health effects of certain conditions (in this case nutritional and genetic) in the group setting. This kind of approach presents some advantages, if the data is readily available, such as being an inexpensive and fast approach to provide an early exploration of an association.
On the other hand, the fact that ecological studies in epidemiology are characterized by their observation unit being a population group and not individuals separately, it is a limitation that could entail some biases. Thus, there is no direct evidence to show that exposures to independent factors (such as suboptimal intakes of different nutrients or genetic variants of risk to suboptimal status of specific nutrient) and the incidence or mortality from COVID-19 occur in the same people, but rather that the results are based on comparisons made in general population groups. Furthermore, the application of the ecological study approach implies that the relationships analyzed cannot be adjusted for other factors that might have an impact on the differences in the incidence and death rates from COVID-19 in these countries. Some of these confounding factors not analyzed here could be socioeconomic factors, age of individuals, levels of air pollution, incidence of respiratory and metabolic diseases in the population, and other factors.
In conclusion, this report considers the potential influence of the 10 essential nutrients, considered critical by the EFSA for the proper functioning of the immune system, by reviewing their potential preventive or other effects against COVID-19. In this context, it is worth noting that the countries with the worst intake profile for these micronutrients correspond to those that have received the cruelest blow from the COVID-19 pandemic. The results of this ecological study show that the suboptimal consumption of Vitamin D, Vitamin C, Vitamin B12, and iron is correlated with either COVID-19 incidence or mortality indicators. Moreover, the scientific evidence accumulated to date highlights the relevance of the optimal status of the 10 nutrients but, above all, it underlines the importance of Vitamin D and iron for the immune system as well as for the prevention and fight against COVID-19. Thus, the body of evidence suggests conducting epidemiological scientific studies, intervention studies, and/or in vitro approaches in order to establish and characterize the benefits of Vitamin D and iron (or even their combination) against COVID-19.
In addition, genetic factors that predispose their carrier to a suboptimal nutritional status for these specific nutrients must be taken into consideration. The analysis of genetic variants associated with lower bioavailability (or lower circulating levels) of essential micronutrients for the optimal functioning of the immune system emerges as a potential and useful tool to detect population groups predisposed to suboptimal phenotypes. Therefore, the detection of individuals with a high genetic risk of showing low levels of specific nutrients would enable the preventive application of personalized nutritional guidelines to promote, in the first instance, individual health, and, as such, improve population health.
Thus, both suboptimal intake and genetic risk of suboptimal status should be screened, and consequent nutrigenetic strategies must be put in place to help individuals to reach an optimal nutritional state and, consequently, improve the whole population’s immunity to face this pandemic.