key: cord-0918121-q7tpi311
authors: Zelka, Fatmanur Zehra; Kocatürk, Rümeysa Rabia; Özcan, Öznur Özge; Karahan, Mesut
title: Can Nutritional Supports Beneficial in Other Viral Diseases Be Favorable for COVID-19?
date: 2022-01-20
journal: Korean J Fam Med
DOI: 10.4082/kjfm.20.0134
sha: 0dc3c7707be6c77774d04993fba709cd2610078b
doc_id: 918121
cord_uid: q7tpi311

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV-2), has rapidly spread worldwide, causing many deaths, the number of which continues to increase. Global public health organizations and governments have advised on the adoption of various handwashing and hygiene guidelines, use of masks, and social distancing, along with isolation or lockdown protocols to prevent SARS-COV-2 spread. There are vaccines and drugs that are confirmed but still many human suffer from this disease. Important risk factors for SARS-COV-2 infection are similar to other viral infectious diseases as including influenza, hepatitis B, acquired immunodeficiency syndrome, and other lung infections. These diseases might be related to poor nutritional support, affecting the patient outcomes against COVID-19. In this review, we discuss some of the nutritional therapies currently being investigated for infectious diseases. Studies have shown that nutrition has the potential to prevent and mitigate viral infections. Micronutrients (vitamins A, B6, B12, C, D, and E, B9, and trace elements, such as iron, zinc, copper, selenium, magnesium, and polyphenols) and macronutrients (carbohydrates, prebiotics, probiotics, protein [amino acids], and lipids [fatty acids]) affect the whole body, including the immune system, preventing viral entry and modulating clinical symptoms. This review discusses the importance of nutrition as a strategy to understand food groups and key nutrients that may affect the clinical outcomes of COVID-19 patients during the ongoing pandemic. Scientists believe that the likelihood of another pandemic is imminent. COVID-19 remains important and scientists believe it will continue will in the future. We emphasize the lack of studies on the nutritional impact of COVID-19 in terms of nutrition, even though nutritional interventions has been shown to have many advantages during the treatment of viral infections.

The new type of coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) was first detected in Wuhan (Hu- bei province), China, in 2019. 1) SARS-COV-2 became a global human threat and the infection caused by it, coronavirus disease 2019 (COV-ID- 19) , was declared a pandemic, 2) with 5,51 million total confirmed deaths by January 12, 2022 . 3) The emergence and rapid spread of new variants of SARS-COV-2 have further increased the global health threat in recent months. 4) COVID-19 symptoms range from mild to severe symptoms that can lead to death. Symptoms including cough, fever, pneumonia, and shortness of breath usually appear for 2-14 days after viral exposure and infection. The infected individuals may also show hepatic, respiratory, neurological, and gastrointestinal complications that can eventually lead to death. [5] [6] [7] [8] Elderly patients and those who required intensive care support mostly had multiple comorbidities, including cardiovascular, cerebrovascular, endocrine, digestive, and respiratory diseases. 5, 9) Though young and healthy people do not fall under major risk groups, they could act as carriers affecting the higherrisk groups. 5, 10, 11) Therefore, standard public health practices have been advised to help decrease exposure and avoid spreading these respiratory viruses. [11] [12] [13] Immunization with a vaccine that stimulates the immune system is the best way to avoid contracting COVID- 19, prevent infection, and reduce mortality. Unfortunately, although there are approved vaccine agents and drug studies, SARS-COV-2 has not prevented its progression. [14] [15] [16] To support the immune system and avoid the adverse effects of viral infection, additional strategies need to be identified; in this respect, nutrition can be supportive. 17) Substantial evidence highlights the effects of diet on the immune system and combating illnesses. It has been shown that particular nutrient supplements can affect the immune system through molecular signaling modifications, gene expression, cell activation, and gut microbial composition determinants. 18, 19) Nutritional insufficiencies in terms of energy intake, protein intake, and specific micronutrient intake are associated with a suppressed immune system function and are highly associated with increased sensitivity to infection. The continuity of the immune system functions is highly dependent on the adequate intake of micronutrients such as zinc (Zn), iron (Fe), copper (Cu), selenium (Se), magnesium (Mg), and vitamins A, B6, B12, and E. 20, 21) To date, there are studies available on the effect of nutrition, disease symptoms and immune system and viral entry on COVID-19 patients. 22) However, in the context of other viral diseases that have been examined, nutrition may be a key factor that may affect the outcomes of COVID-19. International commissions, especially in China, advise that sufficient energy intake from foods and vitamins can improve disease outcomes. 23) This review discusses the importance of nutrition symptom of lymphopenia, which is directly proportional to the severity of the existing infection. [25] [26] [27] [28] [29] [30] Lymphopenia is also observed in conjunction with an increase in neutrophil count and neutrophil-lymphocyte ratio, higher disease severity, and poor prognosis. 29) Receptor CD94/NK group 2 member A is noteworthy in COVID-19like patients. This receptor is known to cause a decrease in NK and CD8+ T cell counts. Additionally, peripheral CD4+ and CD8+ T cells decreased, and hyperactivation was observed in COVID-19 patients.

In these patients, complex cells such as CD3+ T and CD4+ T, as well as cytotoxic granules in CD8 + T cells, were also identified. The presence of these cells is an indication of excessive T cell activation and antiviral immune response. 26, [31] [32] [33] In clinical studies on COVID-19 patients, analysis of blood serum found increased immunoglobulin G response and a higher total antibody titer relative to healthy controls. However, these results were associated with poor prognosis in patients. 29 with severe COVID-19 present   with high levels of IL-6, IFN-α, CCL5, CXCL8, and CXCL10 in the serum compared to those with mild or moderate disease. Severe symptoms are also associated with high IL-6 levels and IL-1β, in addition to   pro-inflammatory levels of IL-2, IL-8, IL-17, granulocyte-colony stimu- lating factor, granulocyte macrophage-colony-stimulating factor, interferon-bound protein 10, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1 a (also known as CCL3); TNF levels were also found to be significantly high in the clinical studies. [25] [26] [27] [28] 38) Highly saturated fatty acids are the building blocks of lipids. It leads to chronic activation of the innate immune system, can activate the innate immune system through the activation of TLRs (e.g., TLR4) expressed on neutrophils and induce a lipotoxic condition. It provides stimulation of macrophages, dendritic cells, and canonical inflammatory signaling pathways that produce proinflammatory mediators and other effectors of the innate immune system in the body.

Highly saturated fatty acids induce oxidative stress. It impairs the proliferation and maturation of T and B cells. In particular, it prevents the B cell from functioning, causing apoptosis of the lymphocyte. It is generally responsible for the suppression of the adaptive immune system. 44, 45) PUFA, n3PUFA PUFAs are another composition that forms lipids and are unsaturated fatty acids. It shows antiinflammatory and immune regulating effects.

Long chain PUFAs, unlike high saturated fatty acids, regulate adaptive immune responses and have a mediating role in the formation of these responses. 41, 46) Carbohydrates Carbohydrates are considered the main nutrient of the body and maintain blood sugar during exercise. It provides lower release of stress hormones, affects the inflammation caused by innate immunity after exercise and associated immune changes. Energy is required for adequate immune response to occur, to perform macrophages, neutrophils and their immunological roles. This energy provides the formation of adenosine triphosphate by using glucose in mitochondria. Therefore, carbohydrates have an important role for immune cells.

Carbohydrates are energizing compounds. It has effects on T and B lymphocytes. It has a key role for an adequate adaptive immune response. 41, 47, 48) Probiotics, prebiotics Probiotics are living microorganisms found in fermented nutrients, and prebiotics are nutrients that contain substances that the human body cannot digest. It improves intestinal microbial flora, thereby increasing immune function and response with a reduction in rates of infection.

Probiotics and prebiotics have effects on T regulatory cells, effector lymphocytes, natural killer T cells and B cells in the adaptive immune system. It takes part in the regulation of the adaptive immune system. 41, 49) Proteins (amino acids) Proteins are structures made up of amino acids. Amino acids have important roles in the immune system. It supports innate immune systems, including stimulation of immune cell function, as in neutrophils.

Proteins contain amino acids in their structure and these amino acids have many immune system supporting roles. In particular, its immunomodulatory role is remarkable. It has positive effects on T cell proliferation and activation. 43, 50, 51) TLR, tolllike receptor; PUFA, polyunsaturated fatty acids. In the presence of vitamin, A, the work of adaptive immune system cells T and B lymphocytes is regulated. This vitamin is necessary to produce antibody responses to the antigen. It also has an active role in many responses, from the development and differentiation of Th such as Th1 and Th2 cells. For example, supporting Th2 antiinflammatory response. 52, 53) Vitamin B6, vitamin B12

Vitamin B6 plays a role in the activation of NK cells and also helps regulate inflammation, as well as have roles in producing inflammatory cytokines. Vitamin B12 has a big role in regulating NK cell functions, and it also has important functions in many systems, including the nervous system.

B6 has many different functions at the adaptive immune system from the endogenous synthesis and metabolism of amino acids, the building blocks of cytokines and antibodies, lymphocyte proliferation, differentiation and to maturation, and this vitamin is also helping maintain immune response with Th1 cells and plays a role in antibody production. Vitamin B12 has the following roles in cellular and adaptive immunity: production of T lymphocytes, influence of CD8+T cells that act as immunomodulators, affecting the single carbon metabolism that the interactions with folate is involved.

Vitamin C Vitamin C supports the integrity of epithelial barriers with its role in collagen synthesis, stimulates production, functioning and movement of leukocytes in innate immunity. It increases the serum levels of complementary proteins such as neutrophils, lymphocytes, phagocytes. They have roles in NK cell activities and have roles in stimulate macrophages for chemotaxis, apoptosis, and removal of spent neutrophils from the sites of infection. It shows antimicrobial effect. It also acts as a protective antioxidant against ROS and RNS that occur during the immune system's destruction of pathogens.

Vitamin C can increase the serum levels of B and T antibodies in the adaptive immune system and play an active role in the differentiation and proliferation of lymphocytes. 52, 53, 56, 57) Vitamin D Vitamin D has many effects on innate immune cells. One of them is that it increases numbers in monocytes, macrophages, dendritic cells. In addition, vitamin D may increase immune cell proliferation and differentiation of monocytes into macrophages. Vitamin D its known to regulate the synthesis of the antimicrobial proteins Cathelicidin and Defensin. These proteins have the capacity to directly kill pathogens, especially bacteria. It also stimulates cytokine production and helps protect from the infections caused by active pathogens.

Vitamin D has a fundamentally inhibitory effects on adaptive immune cells such as T and B lymphocytes. Such as inhibits antibody production by stimulating B cells and also inhibits T cell reproduction 52, 53) Vitamin E Vitamin E has an important antioxidative role in innate immunity. It increases IL2 production and cytotoxic activities of NK cells that uses in infectious diseases, and its antioxidative properties help protect the integrity of cell membranes from damage caused by free radicals.

Vitamin E regulates the functions mediated by the T lymphocyte cell in the adaptive immune system, ensures lymphocyte proliferation and has effects on T helper cells. For example, it optimizes Th1 but also improves and suppresses the Th2 response. 52, 53) Polyphenols Polyphenols are a group containing many bioactive chemicals. Many diseases such as general mortality, chronic health conditions, acute respiratory disease and chronic inflammations have been alleviated in high dietary intake of polyphenols. Its contribution to innate immunity controls NK cell activities, macrophage inflammatory responses, as well as has antiviral effects.

Regulatory T (Treg) cells are cells that help restrain the immune system and prevent excessive T Cell response. Polyphenols play an active role in modulating Treg cells. 58, 59) Folate Folate plays an active role in the protection of innate immunity, especially it helps protect NK cells. Besides, folate has many positive effects on human health.

Folate has important roles in cellmediated immunity, namely in the adaptive immune system, for adequate antibody response to antigens and has effects on T helper cells. For example, folate supports the formation of Th1 mediated immune response. 52, 54) Copper Copper is an antimicrobial and antioxidant trace element. It accumulates in the areas of inflammation and is involved in the fight against bacterial infections in the innate immune system. It is also important for IL2 production.

Copper plays a role in the proliferation of T lymphocyte cells in the adaptive immune system. Copper plays a role in the production of antibodies to B lymphocytes and has an active role in cellular immunity. 53, 54, 60, 61) Iron Iron is a trace element helps kill the bacteria by controlling process of neutrophil cells which are important in the formation of ROS, which kill pathogens. Vitamin D plays a role in the production of cytokines, and also plays a role in killing pathogens by creating highly toxic hydroxyl radicals.

Iron has many roles in adaptive immunity. It plays a role as a component of critical enzymes for the functioning of immune cells, which are essential for cell differentiation and growth, and have roles in lymphocyte differentiation and growth. It is a component of the ribonucleotide reductase enzyme, which is especially involved in DNA synthesis. It is effective in the synthesis of T lymphocytes. 52 

Well-balanced nutrition and hydration are vital for a stronger immune system and lowering the risk of chronic illnesses and infectious diseases. It is essential to consume adequate micro-and macronutrients that the body needs, avoid excess sugar, fat, and salt, and drink enough water to significantly lower the risk of many health problems. 40 In a study of influenza vaccination with oral gummy intake (vitamin A 20,000 IU and vitamin D 2,000 IU), children were found to have increased antibody response. 63 Selenium is an important trace element, it has roles in T lymphocyte proliferation, and has roles in the humoral system, such as the production of immunoglobulin. 52, 54, 60) Zinc Zinc trace element acts as an antioxidant that protects against ROS and RNS. It also helps maintain skin and mucosal membrane integrity for the innate immune system.

Zinc is important for the component of critical enzymes such as ribonucleotide reductase enzyme involved in DNA synthesis for the functioning of adaptive immune cells. This trace element helps modulate cytokine release so it can control acute respiratory distress syndrome as well as induce proliferation of CD8+T cells. 52 Complement system is activated, either by: -Antibody-antigen (i.e., immune) complexes on pathogen surfaces -Mannose-binding lectin binding to mannose on pathogen surfaces -C3, which reacts directly with pathogen surface All complement pathways generate enzyme C3 convertase, to cleave C3 -C3a augments inflammatory response -C3b causes opsonization -C5b triggers formation of MAC, resulting in osmotic lysis Antimicrobial substances discourage microbial growth -Complement mainly provides bacterial immunity -Interferons play a similar role in v ral infections Proinflammatory cytokines also released, to mediate acute inflammatory response -Includes ILs, TNFs, chemokines (e.g., MCP-1), IFN i g Bridges the gap when innate response can no longer cope and the adaptive response is just starting Triggered by innate immune cells, proinflammatory cytokines (e.g., ILs, TNF-a, IFN , GM-CSF) and complement Causes vasodilation, increased vascular permeability, release of inflammatory mediators (e.g., bradykinins, prostaglandins), neutrophil chemotaxis, microvascular coagulation, fever, raised inflammatory markers (e.g., CRP), and upregulation of costimulatory molecules (e.g., MHC-II, B7) that encourage activation of adaptive response g Specific immune response when innate immunity and inflammation can no longer cope with infection -Dendritic cells present antigens to naive T helper cells via MHC-II complexes -Naive T helper cells are fully activated after second signal from APCs -Likelihood of T helper cell activation increased by inflammatory response T helper cells then differentiate to:

-TH1 cells-promote cytotoxic T cells and cell-mediated immunity -TH2 cells-promote B cells and humoral immunity

-Neutralize toxins by directly binding to them -Bind to antigens on pathogen surfaces, triggering agglutinization to impair mobility and opsonization to enhance phagocytosis -Bind to antigens to form complexes that activate complement pathway -Directly activate effector cells such as dendritic cells, NK cells, cytotoxic, T cells TH1 cells active APCs and cytotoxic T cell response Immature T cells must express CD3 and CD4 ro CD8 (never both) and bind to MHC complexes-those that fail immunological tolerance (selftolerance) selection process are destroyed Activation of APCs:

-TH1 cells recognize MHC II-restricted antigen on infected APC and activate it -Once activated, APCs increase production of NO and superoxide radicals-optimizes killing mechanisms and effective destruction of pathogens Cytotoxic T-cell response:

-Activated APCs present antigen to specific cytotoxic T cell receptor within MHC I, along with second signals-aided by IL2, 

The pathogenesis of COVID-19 is known to affect the respiratory system in most patients. 73 

In an in vitro study, the application of UV light and vitamin B2 in MERS-COV infection were tested with pooled plasma (n=3) and repeated with plasma units (n=6). The infectious titer was reduced below the detection limit after treatment; mean log reductions in viral titers were ≥4.07 and ≥4.42 for collected and individual donor plasma.

This study suggests that treatment with UV light and vitamin B2 may reduce the risk of MERS-COV transfusion and transmission. 84) Treatment with vitamin B3 in ventilator-induced lung injury in mouse models has been found to inhibit neutrophil infiltration into the lungs with a strong anti-inflammatory effect. However, this approach should be used with caution, as it can lead to significant hypoxemia. 85 

Vitamin C is an antioxidant. In one study, 200 mg/d of vitamin C was administered to hospitalized elderly patients with acute respiratory infections. Improvement in respiratory symptoms was achieved in patients, and 80% fewer deaths were found in the patient groups receiving vitamin C. In three human-controlled studies, the incidence of pneumonia was significantly lower in the groups supplemented with vitamin C. These findings show that vitamin C may effectively reduce 73, 87, 88) and these results may help address COVID-19. In addition, intravenous vitamin C plays an effective role in treating polio, though magnesium chloride is more effective than vitamin C in polio. 89, 90) However, in a randomized, doubleblind, placebo-controlled, multicenter trial, in patients with sepsis and ARDS supplemented with vitamin C, no specific differences were found compared with placebo and experimental groups. According to the Sequential Organ Failure Assessment score, the score of the group that received vitamin C decreased by 3 points, whereas that of the placebo group decreased by 3.5 points. Furthermore, significant results

were found in parameters such as inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels), which showed only a small difference between the placebo and experimental groups.

In addition, vitamin C does not affect parameters such as altered markers of inflammation or organ dysfunction score improvement, vascular injury, or sepsis in ARDS patients. 91) More clinical studies are needed to investigate the effects of vitamin C on these diseases.

Vitamin D is an important vitamin to fight against pathogens. It is assumed to reduce the incidence and risk of death in influenza and CO- 

In a study conducted with low concentrations of Zn and pyrithione However, there was a decrease in mortality (P=0.02) and a decrease in MV time (P=0.03) in the ongoing omega 3 intake. These results indicate that omega-3 supplementation will produce positive results in patients with ARDS. 105) It can also be considered a potential intervention for omega-3 disease, in conjunction with protein D1, which acts as an antiviral drug. 21, 86) In an adequate and balanced diet, attention should be paid to calorie intake and consumption of macronutrients, vitamins, and minerals, which may potentially benefit patients COVID-19 due to their antiinflammatory and antioxidant properties. 101, 104) Therefore, nutritional support might positively affect COVID-19 symptoms.

In this review, we summarize the impact of nutrition on the immune response and its positive effects on the clinical outcomes of infectious diseases. We found that nutrition is critical in increasing the immune response, limiting viral entry, modifying clinical symptoms, and extending patient survival against RNA viral infections. It is possible that following a diet according to its immune-and symptom-related properties could be useful in protecting against severe infections in patients with COVID-19. Insufficient intake of macro-and micronutrients may increase susceptibility to infections during the COVID-19 pandemic; 54, 71) therefore, this phenomenon should be investigated by further studies.

Lifestyle habits, such as ensuring proper nutrition, are of great importance in developing resistance against infectious diseases such as COVID-19. Unhealthy diets may cause the pre-existing condition to become more chronic in patients with severe symptoms of COVID-19.

For this reason, both patients and healthy individuals should pay attention to their nutritional intake during the pandemic. To prevent or recover from COVID-19, it is recommended that patients avoid satu-rated fat and high-sugar food and consume high amounts of unsaturated fats and antioxidants to strengthen their immune systems to cope with the disease. 71, 102, 106) Adequate intake of energy, macronutrients, vitamins, and minerals is highly recommended. Additionally, some supplements can be advantageous for the host immune system and clinical outcomes in COVID-19. There are many controversial studies in this field, but some studies provide evidence to support the fact that supplements can be beneficial in reducing the side effects of the disease. Therefore, we suggest that in results of these studies should be immediately be validated in the clinical setting. COVID-19 continues its weight and seems to continue its impact. Therefore, nutritional measures should be taken to overcome the difficulty of the disease and its effects after suffering the disease.

No potential conflict of interest relevant to this article was reported.

Fatmanur Zehra Zelka: https://orcid.org/0000-0001-7791-7763

Rümeysa Rabia Kocatürk: https://orcid.org/0000-0001-6769-3057

Öznur Özge Özcan: https://orcid.org/0000-0001-8992-0556

Mesut Karahan: https://orcid.org/0000-0002-8971-678X

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