key: cord-0778197-yaab1j2q authors: Calcuttawala, Fatema title: Nutrition as a key to boost immunity against COVID-19 date: 2022-04-15 journal: Clin Nutr ESPEN DOI: 10.1016/j.clnesp.2022.04.007 sha: 684e900128792c2c6b9951ebdfb6effc881c62ea doc_id: 778197 cord_uid: yaab1j2q The Coronavirus-disease 2019 (COVID-19) was declared as a global pandemic on March 11, 2020 by the World Health Organization. Since then, the scientific community has been actively engaged in developing a vaccine against the dreaded disease. Considerable research has also been performed for drugs that can directly interfere with the viral replication pathway. However, the production of these vaccines and drugs demands a lot of time and effort which is undesirable considering the pace at which the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spreading across the continents. For this reason, the possible role of dietary nutrients in reducing the risk of SARS-CoV-2 infection as well as mitigating the symptoms, may be explored. These natural substances are readily available, have negligible side effects and confer several benefits to the immune system. Macronutrients like proteins are vital for antibody production. Dietary constituents such as omega-3-fatty acids, vitamin C, vitamin E, phytochemicals such as carotenoids and polyphenols exhibit anti-inflammatory and antioxidant properties. This review highlights the significance of relevant nutrients in boosting the immune system. acids which are then reassembled into antibodies and complement proteins that are the major players of the immune system. Amino acids play a major role in regulating the activation of macrophages, natural killer cells, B and T lymphocytes. They are important for the production of cytokines and cytotoxic substances [13] . Amino acids also regulate key metabolic pathways of the immune response against infectious pathogens. The normal sustainance of immunocompetence requires adequate dietary provision of all amino acids. A protein deficient diet leads to an impaired immunity which in turn is directly related to an increase in COVID-19 infection risk. Amino acids like arginine and glutamine are very important in stimulating the immune system. Proteins of high biological value which contain essential amino acids and from healthy dietary sources such as from eggs, poultry, meat and fish also constitute an essential component of an anti-inflammatory diet [14] . Fatty acids in the diet significantly influence the immune response. Omega-3 and omega-6 fatty acids are two essential fatty acids which need to be consumed in the diet as the human body cannot synthesize them. The omega-3 fatty acids largely comprise of α-linolenic acid (ALA) from plant sources and docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) from fish and seafood sources. The dietary intake of these omega-3 fatty acids has been demonstrated to trigger antiinflammatory reactions in the body [15] . On the other hand, omega-6 fatty acids such as arachidonic acid is a precursor of pro-inflammatory eicosanoids like prostaglandins and leukotrienes. High levels of omega-6 fats are found in refined vegetable oils and also in nuts and seeds. A healthy ratio of omega-6/omega-3 fatty acids is between 1:1 -4:1. Omega-6 fats provide energy to the body but people should ideally consume more omega-3 fats [16] (Fig. 1 ). Omega-3 J o u r n a l P r e -p r o o f fatty acids change the composition of the phospholipid bilayer of the host cell membrane, thereby preventing viral entry. DHA and EPA get incorporated in the plasma membrane and affect the clumping of toll-like receptors. This results in prevention of signals that activate NF-κB, production of fewer pro-inflammatory mediators and eventually reduction in complications of COVID-19 infection. DHA and EPA also serve as precursors of resolvins D and E which reduce the production of pro-inflammatory mediators eventually resulting in a decrease in lung inflammation [17]. Carbohydrate consumption has been reported to increase serotonin production, which in turn has a positive impact on a person's mood [18] . Thus, carbohydrate-rich foods have an anti-stress, selfmedicating effect. However the amount of carbohydrates in the diet needs to be regulated as excess carbohydrates may lead to obesity, diabetes and heart diseases which may increase the complications due to COVID-19 infection [19] . Dietary fiber is the portion of plant-derived food or analogous carbohydrates that cannot be completely broken down by human digestive enzymes. The dietary fiber has been found to have a prebiotic effect such as fostering the growth of beneficial microbes like Bifidobacterium sp. and Lactobacillus sp. and inhibiting the pathogens like Clostridium sp [20] (Fig. 1 immune responses, down regulates the production of pro-inflammatory cytokines and inflammation and also improves respiratory function considerably [25] . B vitamins also reduce gastrointestinal problems, prevent hypercoagulability and reduce the duration of hospital stay for Vitamin C is a classical antioxidant which has a significant impact on the immune system. It influences the activity of phagocytes and T-lymphocytes (Table 1) . Ascorbic acid in the diet has been reported to lower the concentration of C-reactive protein. Vitamin C has been postulated to exhibit antiviral activity by augmenting the production of interferon proteins [26] . Given the antioxidant and antiviral effect of vitamin C and its favorable safety profile it may be an effective Thirdly vitamin D boosts the adaptive immunity by reducing the production of pro-inflammatory cytokines by TH1 cells and increasing the production anti-inflammatory cytokines by TH2 cells [27] (Fig. 2 ). Low levels of vitamin D are reported in many adults at the end of the winter season due to a limited exposure to sunlight. There is an observed difference in mortality due to COVID-19 between Northern Hemisphere and Southern Hemisphere [28] . This indicates a possible role of vitamin D in governing the pathogenesis of COVID-19. Vitamin E is a fat-soluble vitamin which includes both tocopherols and tocotrienols. It is a potent antioxidant. Vitamin E has been demonstrated to regulate the immune response by modulating the TH1/TH2 balance and initiation of T-lymphocyte signals [29] (Table 1) . Vitamin E not only acts through anti-oxidant pathways to increase the number of T cells but it also increases mitogenic lymphocyte responses, IL-2 cytokine secretion, activity of natural killer cells and eventually decreases the risk of COVID-19 infection [30] . Zinc is an essential micronutrient which is required as a co-factor for many enzymes involved in antioxidant reactions ( Table 1 ). The deficiency of zinc causes oxidative stress and also influences both the natural and acquired immunity. It has been reported that a low zinc status increases the Several antioxidant enzymes such as glutathione peroxidase, selenoprotein P, and thioredoxin reductase require the trace element selenium for their synthesis [33] . Thus, the primary role of selenium is its ability to act as an antioxidant and quench the reactive oxygen species (ROS) ( Table 1 ). Dietary selenium deficiency has been associated with a high level of pathogenicity of several viruses [34, 35] . The cure rate for COVID-19 was found to be significantly higher in patients with a high selenium intake in the diet [36] . Studies have proven that a supra nutritional levels of selenium might suppress not only the life cycle of SARS-CoV-2 but also its mutation to a more virulent form. This is because of the fact that both selenoproteins as well as redox-active selenium species in the selenium metabolic pool attenuate viral-induced oxidative stress, cytokine storm and organ damage. Another study has proven that sodium selenite oxidizes the thiol groups in the protein disulfide isomerase of the coronavirus, thereby rendering it incapable of penetrating the host cell membrane [37] Iron homeostasis is tightly regulated during bacterial and viral infections. When there is an inflammatory response, iron absorption is decreased so as to limit the pool of iron available to the multiplying bacteria and viruses. However, some studies have demonstrated that during a prolonged period of iron deficiency, antibody production is considerably reduced. Iron also plays an important role in T-cell proliferation and maturation as well as regulation of cytokine production [38] ( Table 1) . A study has implicated the role of hyperferritinemia and an increased inflammatory state in COVID-19 pathogenesis [38]. Polyphenols are phenolic compounds derived from plants which are enriched with antioxidant and anti-inflammatory properties. Dietary polyphenols are broadly classified into four groups which comprise of phenolic acids, lignans, stilbenes and flavonoids (Fig. 3) . Several polyphenols, for example the flavonoid quercetin exhibits antiviral properties [39] . Quercetin has been reported to decrease viral infectivity and hampers intracellular viral replication [26] . There is a plethora of infection [40, 41] . J o u r n a l P r e -p r o o f Carotenoids are tetraterpenoids. They include orange, red and yellow organic pigments produced by plants, algae and bacteria. Some of the common carotenoids are α-and β-carotene, lutein, zeaxanthin and lycopene (Fig. 3) . Carotenoids are well known for their antioxidant properties and quenching of ROS. Thus, low levels of carotenoids are associated with oxidative stress. Antiviral roles of lutein, carotene and zeaxanthin have been reported. Some carotenoids serve as a precursor of vitamin A which is directly associated with immunomodulating functions [42] . It has been reported that carotenoids alleviate the inflammatory responses that lead to lung damage during COVID-19 infection [43] . Calories come from carbohydrates, (1 g yields 4 calories), fats (1 g gives 9 calories) and proteins (1 g yields 4 calories) [12] . Non protein calorie refers to the combined energy from lipids and carbohydrates. As protein is the only macronutrient which provides nitrogen, non protein calorieto-nitrogen ratio (NPC:N) may be used to assess whether nitrogen or protein intake is sufficient to maintain muscle tissue. It describes the balance between energy and protein. Proteins are composed of 16% nitrogen. A NPC:N ratio of 150:1 to 200:1 is adequate for stable patients. However for critically ill patients or those who are having difficulty in maintaining muscle mass, a higher protein intake is optimal and a NPC:N ratio of 100:1 or lesser is desirable [46] . About 5% of patients suffering from COVID-19 develop an acute respiratory distress syndrome (ARDS) and require respiratory support in critical care units. As per the clinical guidelines, nutritional support should be started within the first 48 hours of admission to the intensive care unit (ICU) along with enteral nutrition (EN) [46] . By the end of the first week of admission to the ICU, the caloric and protein target should be reached. In case the patient is incompatible with EN, parenteral nutrition (PN) should be started after 3rd to 7th day of admission to the ICU. One such study was conducted in a tertiary hospital in Madrid which was severely hit by the pandemic in the first wave [47] . In that retrospective study, spanning a period from March to May, 2020, medical nutrition treatment (MNT) was given to critically ill patients with COVID-19 and the J o u r n a l P r e -p r o o f clinical outcome was monitored closely. The variables recorded comprised of age, sex, body mass index (BMI), comorbidities mainly like obesity, hypertension, diabetes and date of admission to the ICU [48] . The type of respiratory support being provided such as invasive mechanical ventilation (IMV), high flow nasal cannula (HFNC) or non invasive ventilation (non-IMV) was noted. The caloric or energy requirement was calculated by 25 kcal/kg adjusted body weight (ABW) and the protein requirement as 1.3 g/kg ABW/day. On the 4th and 7th day of admission to the ICU, energy and protein administered were calculated. This also took into account the calories provided in the form of propofol administration. The MNT type provided was either EN, PN or mixed EN+PN. Patients were also closely monitored for metabolic complications and acute kidney failure (AKF) [49] . Eventually, their length of the stay (LOS) at the hospital or the mortality was recorded. A total of 176 patients were included in the study. Majority of them met the energy and protein requirements during the first week of admission to the ICU by the use of PN or PN+EN. Thus, PN can be used safely alongwith EN in critically ill patients with COVID-19 by closely monitoring them for metabolic complications [49] . Malnutrition has harmful consequences on COVID-19 patients. Thus, nutritional care of these patients cannot be overlooked. Early nutritional supplementation of non-critically ill COVID-19 patients who have been hospitalized is also very crucial. The nutritional status of these patients should be enhanced at the time of admission itself [50] . Nutritional support, mainly protein intake cholecalciferol should be administered. If the patient is unable to eat or incompatible with ONS then parenteral nutrition is prescribed [50] . This review focuses on the interactions of the various macronutrients, micronutrients and phytochemicals with the immune system and its relevance during the COVID-19 crisis. Research indicates that a high protein diet facilitates antibody production [12] . A diet enriched in omega-3 fatty acids, vitamins and minerals is highly recommended during this pandemic situation ( Table 2 ). In the present-day scenario where many research groups are actively engaged in developing vaccines and novel therapeutics against COVID-19, a balanced nutrient status which reduces inflammation and oxidative stress may strengthen the immune system and thus may be the key to No funding was received to assist with the preparation of this manuscript. The author has no conflicts of interest to declare that are relevant to the content of this article. Legends to Figures Fig. 1 Nutritional significance of macronutrients The SARS-CoV-2 outbreak: What we know The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Angiotensin Converting Enzyme 2: A Double-Edged Sword Could Vitamins Help in the Fight Against COVID-19? 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Probiotics and Covid-19 Singer P; endorsed by the ESPEN Council. ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection Nutritional management and clinical outcome of critically ill patients with COVID-19: A retrospective study in a tertiary hospital ESPEN guidelines on nutritional support for polymorbid internal medicine patients Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial Early nutritional supplementation in non-critically ill patients hospitalized for the I would like to acknowledge Abdulkadir Raja for providing valuable assistance in writing this article.