Review Article | Open Access
Mariangela Rondanelli, Alessandra Miccono, Silvia Lamburghini, Ilaria Avanzato, Antonella Riva, Pietro Allegrini, Milena Anna Faliva, Gabriella Peroni, Mara Nichetti, Simone Perna, "Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds—Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds", Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 5813095, 36 pages, 2018. https://doi.org/10.1155/2018/5813095
Self-Care for Common Colds: The Pivotal Role of Vitamin D, Vitamin C, Zinc, and Echinacea in Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds—Practical Advice on Dosages and on the Time to Take These Nutrients/Botanicals in order to Prevent or Treat Common Colds
Maintaining a normal healthy immune defense system lowers the incidence and/or the severity of symptoms and/or the duration of common cold (CC). Physical barriers and innate and adaptive immunity have been involved during a CC episode. Vitamins C and D, zinc, and Echinacea have evidence-based efficacy on these immune system barriers. This review includes 82 eligible studies to consider the preventive role of these nutrients in immune clusters and in CC to provide advice on dosage and assumption of these nutrients. Regarding vitamin C, regular supplementation (1 to 2 g/day) has shown that vitamin C reduces the duration (in adults by 8%, in children by 14%) and the severity of CC. Considering zinc, the supplementation may shorten the duration of colds by approximately 33%. CC patients may be instructed to try zinc within 24 hours of onset of symptoms. As for vitamin D, the supplementation protected against CC overall, considering baseline levels and age. Patients with vitamin D deficiency and those not receiving bolus doses experienced the most benefit. Regarding Echinacea, prophylactic treatment with this extract (2400 mg/day) over 4 months appeared to be beneficial for preventing/treating CC. In conclusion, the current evidence of efficacy for zinc, vitamins D and C, and Echinacea is so interesting that CC patients may be encouraged to try them for preventing/treating their colds, although further studies are needed on this topic.
Common cold (CC) is a conventional term used for mild upper respiratory illnesses, which comprises a heterogeneous group of self-limited diseases caused by numerous viruses and is the most frequently encountered human diseases worldwide .
In European populations, adults have from 2 to 5 infections annually, children typically present 6 to 12 “colds” per year, and rates of symptomatic infections increase in the elderly . A seasonal variation is present with more episodes in winter and fall  and, on average, episodes of common colds last around 10 days .
Thus, treatments that reduce the incidence of infection and/or lessen the severity of symptoms and/or shorten the duration of common colds are of high interest both for the individual and for the whole society.
Maintaining the immune defense system within a normal healthy state lowers the incidence of infection and/or lessens the severity of symptoms and/or shortens the duration of common colds. Natural killer cell (NK cell) activity and salivary immunoglobulin A (IgA) are considered important in the prevention of common colds . However, several environmental factors, including a stressful lifestyle, are likely to weaken the immune defense system , which may result in an increased risk of common cold. Lifestyles and mental health status are associated with natural killer cell and lymphokine-activated killer cell activities . The immune system is an intricate network of specialized tissues, organs, cells, and chemicals protecting the host from infectious agents and other noxious insults. Although these defense mechanisms are very complex, they can be described as being organized in three main interactive clusters: physical barriers, and innate and adaptive immunity [9, 10].
The first barrier against “invaders” consists of physical barriers (low pH caused by various fatty acids and enzymes; it can limit the growth of most bacteria), mucus secretion (it contains proteins that can destroy pathogens), and the acidity of the stomach. Innate immunity is the second barrier and includes immune system cells, such as NK cells, cytokines (such as interferon-γ), macrophages, and neutrophil granulocytes. In addition, zinc shows its antiviral effects through the Intercellular Adhesion Molecule 1 (ICAM-1). Adaptive immunity is the third barrier to infection and is acquired later in life, such as after an immunization or successfully fighting off an infection. It retains a memory of all the invaders it has faced and this accelerates antibody production . It includes lymphocytes T (e.g., regulatory T cells) and lymphocytes B.
1.1. Mechanism of Innate Immunity (Physical Barriers and Immune Cells) during Common Cold
When a respiratory virus is inhaled it first binds to nonspecific receptors on the respiratory epithelium, usually glycolipids or glycoproteins. Membrane fusion or endocytosis follows, thus internalizing the virus and enabling subsequent replication, transcription, and translation of new viruses which can then be released to infect new cells. Once a cell has been infected, pathogen-associated molecular patterns (PAMPs) on the virus can be recognized by various intracellular innate pathogen recognition receptors (PRRs) such as the toll-like receptors (TLRs), retinoic-acid-inducible gene-I- (RIG-I-) like receptors (RLRs), and nucleotide binding-oligomerization domain (NOD-) like receptors (NLRs) . Pulmonary epithelial cells have been shown to express all of the known human TLRs and RLRs that detect viruses, and ligands for these PRRs activate epithelial cells in order to initiate a rapid immune response against viral invasion . In addition to direct infection of epithelial cells, intraepithelial dendritic cells (DCs) residing just below the respiratory epithelium and tissue-resident macrophages continually sample particles in the airway lumen and can internalize them by phagocytosis and macropinocytosis, thus activating PRRs and initiating an immune response [14, 15].
Features of the induced antiviral state include resistance to viral replication in all cells, induction of apoptotic cell death in infected cells, increased major histocompatibility complex (MHC) class I expression to enhance antigen presentation, activation of dendritic cells (DCs) and macrophages, and stimulation of natural killer (NK) cells to enhance their cytolytic activity . The inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-12 are also produced at an early stage of the innate immune response. These cytokines promote leukocyte extravasation by increasing endothelial expression of adhesion molecules increasing vascular permeability, induce synthesis of acute phase proteins, and contribute to recruitment and activation of cells of the adaptive immune response . Other antimicrobial vitamin D dependent peptides, such as cathelicidins and defensins, are involved in the second barrier.
1.2. Mechanism of Adaptive Immunity (Antibodies) during Common Cold
Around 72 h after infection, DCs with antigen-MHC complexes migrate through the afferent lymph vessels to secondary lymph nodes where they form interactions with naive CD4 and CD8 T lymphocytes. These T lymphocytes activate, proliferate, and differentiate into effector T cells and migrate via efferent lymph vessels into the circulation. Multiple chemokines are expressed in the respiratory epithelium and result in changes in integrin affinity, allowing effector T cells to bind to the endothelium and migrate into the infected tissue [17–19]. For efficient and effective viral clearance Th1 effector T cells are required, which produce IL-2, TNF-α, and IFN-γ to activate NK cells and induce generation of cytolytic molecules. CD8 effector T cells and NK cells can then induce apoptosis of infected cells . B cells have also been demonstrated to play an important role in the immune response to highly pathogenic viral infections. Contact between CD4 T cells and naive B cells in secondary lymphoid tissues results in their proliferation and antibody class-switching, with neutralizing virus-specific antibodies crucial for optimal viral clearance. Additionally, viral components expressed on infected cells allow antibodies to bind, thus initiating antibody-dependent cell-mediated cytotoxicity (ADCC), whereby CD16 on NK cells recognizes the Fc portion of antibodies bound to the surface and kills the target cell [12, 17, 20, 21].
1.3. Self-Care for Common Colds: Role of Nutrition and Botanicals and Their Interaction in Three Main Immune Interactive Clusters: Physical Barriers, Innate and Adaptive Immunity
As common colds have a self-limited course and resolve without treatment, studies on self-care have shown that common colds are the most frequent cause for self-care [22–24]. A variety of alternative and nonpharmacologic treatments of the common cold are proposed [25, 26]. Between these numerous nonpharmacological approaches for prevention and treatment of the common cold, there are the intakes of some nutrients, such as zinc, selenium, iron, copper, b-carotene, vitamins A, D, C, and E, folic acid, and botanicals, such as Echinacea . The proposed biologic mechanisms are that these nutrients can significantly influence several components of immunity . But among these numerous nutrients, which have proven to have evidence-based efficacy on all three immune system barriers? The nutrients are vitamin C, vitamin D, and zinc, because all three nutrients have specific EFSA (European Food Safety Authority) scientific opinion on the substantiation of health claims related to vitamin D , vitamin C , zinc , and normal function of the immune system. Moreover, there is EFSA scientific opinion on the substantiation of health claims related to zinc  and to vitamin C  and maintenance of normal physical barriers, the first immune system barriers. Finally, for vitamin C  and Echinacea  there are Cochrane reviews regarding the use of these two nutrients for preventing and treating the common cold.
Given this background, the purpose of this narrative review is to consider the pivotal role of vitamin D, vitamin C, zinc, and Echinacea on three main immune interactive clusters (physical barriers, innate and adaptive immunity) in terms of prevention and treatment (shortening the duration and/or lessening the severity of symptoms) of common colds in order to provide practice advice on the dosages and on the time to take these nutrients.
The present systematic review was performed following the steps by Egger et al. as follows : (1) A working group was configured as follows: three operators skilled in endocrinology and clinical nutrition, of whom one acting as a methodological operator and two participating as clinical operators. (2) The revision question on the basis of considerations made in the abstract was formulated as follows: “the state of the art on role of vitamin D, vitamin C, zinc, and Echinacea in three main immune clusters (physical barriers, innate and adaptive immunity) in terms of prevention and treatment (shortening the duration and/or lessening the severity of symptoms) of common colds.” (3) Relevant studies were identified as follows: a research strategy was planned, on PubMed [Public Medline run by the National Center of Biotechnology Information (NCBI) of the National Library of Medicine of Bethesda (USA)], as follows: (a) definition of the key words (common cold, Echinacea, immunity, nutrients, vitamin C, vitamin D, and zinc), allowing the definition of the interest field of the documents to be searched, grouped in quotation marks (“…”), and used separately or in combination; (b) use of the Boolean AND operator that allows the establishment of logical relations among concepts; (c) research modalities: advanced search; (d) limits: time limits: papers published in the last 30 years; languages: English; (e) manual search performed by the senior researchers experienced in clinical nutrition through revision of reviews and individual articles on role of vitamin D, vitamin C, zinc, and Echinacea in three main immune interactive clusters (physical barriers, innate and adaptive immunity) in terms of prevention and treatment (shortening the duration and/or lessening the severity of symptoms) of common colds published in journals qualified in the Index Medicus. (4) The analysis was carried out in the form of a narrative review of the reports.
3.1. Zinc and the Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds
This research has been carried out based on the following keywords: “zinc” OR “zinc supplementation” AND “immune response” AND “innate immunity” AND “adaptive immunity” AND “respiratory tract infections” AND “common cold” AND “Immunodeficiency.”
Figure 1 shows the study selection process.
Table 1 summarizes the studies presented in the narrative review.
3.1.1. First Barrier: Physical Barrier
In the present era, approximately two billion people in developing countries suffer from Zn deficiency (ZnD), mainly due to malnutrition and manifest clinical characteristics of growth retardation and compromised immune systems .
Adequate zinc intake helps to maintain physical barriers and mucosal membrane integrity and unbound zinc ions exert a direct antiviral effect on rhinovirus replication . Supplementation of Zn improves immune functions, including delayed cutaneous hypersensitivity in children (10–20 mg of Zn) [36, 37], but other authors do not completely agree [38, 39]. It improves delayed-type hypersensitivity (DTH) in children supplemented with 10 mg/day .
3.1.2. Second Barrier: Cellular Natural Immunity
Zinc supplementation increases cellular components of innate immunity (e.g., phagocytosis by macrophages and neutrophils, natural killer cell activity, and generation of oxidative burst) .(1)Neutrophil granulocytes, macrophages: large amounts of oral zinc significantly impaired polymorphonuclear leukocytes (PMNL) function and, in vitro, zinc potentiated the neutrophil response against Staphylococcus aureus . Zn supplementation (150 mg/d) in elderly also induces a decrease in granulocyte zinc that has implications in phagocytosis and chemotaxis .(2)Natural killer: a supplementation of zinc (in vitro studies or 100 mg/d in elderly) improves natural killer (NK) cells activity, as argued by a lot of authors [9, 11, 39, 42]. Zinc administration decreased peripheral blood NK cell activity in vitro in patients with that inflammatory disease .(3)Cytokine: common cold viruses increase oxidative stress, which activates macrophages and monocytes and results in increased production of both the inflammatory cytokine IL-1α and the anti-inflammatory product IL-1ra . After zinc restriction, there was reduction in the in vitro secretion of interleukin-2 receptor (IL-2R) . Zinc is involved in the cytosolic defense against oxidative stress (superoxide dismutase activity) . Recently, the transcriptional repressor Gfi1, a zinc finger protein, was identified as a regulator of immune response . Inflammatory cytokines, such as tumor necrosis factor α and interleukin (IL) 1, are also known to generate greater amounts of reactive oxygen species and these parameters significantly decrease after zinc supplementation in the elderly (45 mg) . Zn could normalize the production of interleukins, such as IL-2 , but also IL-1, IL-6, and tumor necrosis factor α (TNF-a), by mononuclear cells in vitro . It modulates cytokine release by peripheral blood nuclear cells . Il-6 increased in infants born to mothers that received Zn supplementation . Most important, the ex vivo generation of TNF-α from isolated mononuclear cells (MNCs) is significantly decreased in elderly subjects after zinc supplementation . Finally, Zn has role in the production of interferon-γ . Zinc is involved also in the biosynthesis of leukotriene B4, which is implicated in a variety of acute and chronic inflammation, including chronic-obstructive pulmonary disease (COPD) . The antiviral effects of zinc (5 mg), through the Intercellular Adhesion Molecule 1 (ICAM-1) receptor blocking, have been considered as one of the most important actions for impacting on incidence and/or duration of upper respiratory tract infections (URTI) .
3.1.3. Third Barrier: Adaptive Immunity
Zn is required for proper antigen presentation via MHC-II to elicit adaptive immune responses . Zinc deficiency in experimental animals is associated with low thymic weight and progressive loss of T lymphocytes (T cells) because zinc is an essential cofactor for the thymic hormone thymulin. Thymulin induces several T cell markers and promotes T cell function, including allogenic cytotoxicity, suppressor functions, and interleukin-2 production . Zn supplementation (30 mg/day) is required in order to enhance functions of T cells, thanks to an increase in the production of T cells and/or a decrease in the loss of T cell precursors via apoptosis . It increases the number of CD4 (helper) lymphocytes in children with a 10–20 mg of supplementation  or with 5 mg of zinc  and also CD8 [9, 26]. Since it is an essential cofactor for thymulin , a possible explanation of these effects on T cells is related to thymulin levels, which is required for the differentiation of CD4+ T cells [45, 52]. Another explanation is a direct effect of zinc ion on the lymphocyte membrane affecting maturation and differentiation of T lymphocytes . Zinc acts on T lymphocytes through modulating IL-2 secretion, receptor expression, and sensitivity . Zn controls antibody-mediated humoral immune responses, and a zinc cell-membrane-localized transporter (ZIP10-Zn) has a role in early B-cell development and the maintenance of mature B cells .
3.1.4. Zinc Supplementation for Common Colds
Many studies have agreed that supplementation of zinc is helpful in reducing the risk of pneumonia and common cold and the incidence of respiratory tract infection, specifically in the elderly and in children [9, 33, 36, 50, 53, 54]. Zinc supplementation (20 mg/day) accelerates recovery from severe pneumonia in children . (However, two articles were found which do not support a role for intranasal zinc (gluconate) in prevention or treatment of the common cold or immune parameters [55, 56], but in these two studies the way of administration is intranasal.) Very recently two meta-analyses demonstrated that zinc may shorten the duration of colds by approximately 33% . However, there are some topics about zinc and common cold that are still not clear. In particular, high dosage of zinc in clinical trials has caused adverse effects, such as bad taste, and the variation in the total daily dose of zinc.
In conclusion, given the discreet evidence of efficacy on shortening the duration of colds by approximately 33%, common cold patients may be instructed to try zinc within 24 hours of onset of symptoms . However, since controlled trials that have examined the effect of zinc on the common cold have diverged, the optimal composition and dosage of zinc should be better investigated in addition to the optimum frequency of their administration.
3.2. Vitamin D and Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds
This research has been carried out based on the following keywords: “vitamin D” OR “vitamin D supplementation” AND “immune response” AND “innate immunity” AND “adaptive immunity” AND “respiratory tract infections” AND “common cold” AND “immunodeficiency.”
Figure 1 shows the study selection process.
Table 2 summarizes the studies presented in the narrative review.
3.2.1. First Barrier: Physical Barrier
The active hormone 1,25(OH)2D is important in upregulating genes via the 1a-hydroxylase enzyme, which then encode proteins required for tight junctions (e.g., occludin), gap junctions, and adherens junctions (e.g., E-cadherin) .
Vitamin D supplementation increases cathelicidin production and it is involved in the production of defensins . These antimicrobial peptides are also involved in the second barrier.
3.2.2. Second Barrier: Cellular Natural Immunity
A review by Hewison et al. shows that vitamin D supplementation is successful in raising serum levels of 25OHD in TB patients and it may also play a role in promoting innate immune responses to enhance monocyte phagocytosis and degradation of b-amyloid.
The effects of vitamin D3 on macrophage phagocytosis may be related to the ability of that vitamin to alter monocyte maturation. Thus, D3 enhances immunoglobulin and complement-mediated phagocytosis by human monocytes through its stimulation of monocyte maturation to macrophages .
Enhancing protective innate immune responses, 1,25(OH)2D helps maintain self-tolerance by dampening overly zealous adaptive immune responses.
In addition, oral supplementation with HyD (25(OH)D3 metabolite) at a dose of 20 μg per day may explain the benefit of HyD on systolic blood pressure reduction, improvement in lower extremity function, and the more pronounced reduction in several markers of innate immunity among healthy postmenopausal women .
3.2.3. Third Barrier: Adaptive Immunity
Human epidemiological studies indicate supplementation with 1,25(OH)2D3 as an independent protective factor influencing the occurrence of Th-1 mediated autoimmunity . The effects of 1,25(OH)2D on the immune system include decreasing Th1/Th17 CD4+ T cells and cytokines, increasing regulatory T cells, downregulation of T cell-driven IgG production, and inhibition of dendritic cell differentiation . The adaptive immune effects of vitamin D are not restricted to effector T cells and also include actions on suppressor or regulatory T cells (Treg), a group of CD4+ T cells known for inhibiting the proliferation of other CD4+ T cells. Treatment of naive CD4+ T cells with 1,25(OH)2D potently induces the development of Treg, and this may exert beneficial effects in autoimmune disease and host-graft rejection .
A short term high-dose vitD3 supplementation (140.000 IU) significantly increased the frequency of regulatory T cells (Tregs) but did not further improve β-cell function in apparently healthy subjects.
VitD3 may be a useful therapeutic agent in autoimmune diseases exerting immune modulatory effects involving stimulatory actions on Tregs .
Vitamin D deficiency or insufficiency has immunological implications in patients with recurrent miscarriage (RM). The percentage of B cells, the percentage of TNF-α-producing Th cells, and NK cytotoxicity are significantly reduced under 0.5 μg/day of 1,25(OH)2D supplementation for 2 months . Treatment with 4000 IU vitamin D3 significantly reduced CD4+ T cell activation compared to low-dose vitamin D3, providing human evidence that vitamin D can influence cell-mediated immunity .
Vitamin D associated with upper respiratory tract infections (URI) burden probably involves lymphocytes and their activity. However, thymus activity, represented by higher T cell receptor excision circles (TREC, markers of thymus activity) levels, is not related to vitamin D concentrations or status and is not affected by 2000 IU/d vitamin D supplementation in adolescent swimmers .
3.2.4. Vitamin D and Common Colds
Clinical trials demonstrate that 400 IU/d vitamin D supplementation is needed for the prevention of respiratory infections [67, 68]. Vitamin D supplementation decreases the events related to respiratory tract infections. In particular, vitamin D is useful in prevention of these types of infections, assuming dosage of vitamin D ranging from 400 IU/day to 2000 IU/day . Epidemiologic studies have found high vitamin D levels to be associated with lower risk of infections of the upper respiratory tract (colds). 4000 IE/day vitamin D supplementation is found to significantly increase the probability of staying infection free during the study period. This finding further supports the notion that vitamin D status should be monitored in adult patients with frequent respiratory tract infections, and patients with vitamin D deficiency must be supplemented . The more vitamin D is reserved within the infants’ bodies, the more they will be immune to respiratory infections. It is assumed that the lack of significant differences in vitamin D is due to the gestational age and other factors except that vitamin D deficiency plays crucial roles in respiratory system infections . Supplementation with vitamin D in children seems to be a strong ally in fighting the onset of respiratory infections. The combination of vaccines and vitamin D supplementation can significantly reduce the appearance of URTIs and the use of antibiotics, with a consequent decrease of global indicators of bacterial resistance . In Mongolian children, who received milk fortified with 300 IU of vitamin D3, vitamin D supplementation significantly reduced the risk of acute respiratory infections (ARIs) in winter among children with vitamin D deficiency . Finally, 1200 IU/d vitamin D3 supplementation during the winter may reduce the incidence of influenza A and enhance innate immunity by upregulating antimicrobial peptides, especially in specific subgroups of schoolchildren . Weekly supplementation with 10,000 IU of vitamin D3 is preventive for URTI in young adults .
Vitamin D supplementation is safe and protected against acute respiratory tract infection overall, but patients who are very deficient in vitamin D and those not receiving bolus doses experienced the most benefit, as demonstrated very recently in a meta-analysis that considered 25 eligible randomized controlled trials (total 11,321 participants, aged 0 to 95 years) .
On the other hand, some evidence shows no significant correlation between vitamin D levels and lower respiratory tract infections in terms of the disease and its severity , despite a 50 μg vitamin D3 (2000 IU) daily supplementation . The sub-sunburn sunbed treatment is effective in tanning and increasing the 25(OH)D serum level, more so than 1000 IU per day, but had no appreciable effect on colds . In patients with mild to moderate asthma undergoing an inhaled corticosteroid dose reduction, the use of vitamin D supplementation (100,000 IU load plus 4,000 IU/d) is not supported for the purpose of reducing cold severity or frequency . In addition, monthly administration of 100,000 IU of vitamin D does not reduce the incidence or severity of URTIs in healthy adults . It is reasonable and safe to take approximately 1000 IU of vitamin D daily, as suggested by Zittermann et al., in order to optimize nonspecific immunity and prevent infection. It is important to start supplementation in early autumn in order to ensure an adequate vitamin D level in winter .
In conclusion, vitamin D supplementation was safe and it may protect against acute respiratory tract infections overall, although there are numerous studies that do not support this indication and therefore it is necessary that further research will be conducted on the dosage of intake of vitamin D and prevention/treatment of common cold. Baseline levels of vitamin D, age, and dose of vitamin D need to be taken under consideration in order to personalize therapy. Patients who were very deficient in vitamin D and those not receiving bolus doses experienced the most benefit, and it is important to start supplementation in early autumn in order to ensure an adequate vitamin D level in winter.
3.3. Vitamin C and Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds
This research has been carried out based on the following keywords: “vitamin D” OR “vitamin D supplementation” AND “immune response” AND “innate immunity” AND “adaptive immunity” AND “respiratory tract infections” AND “common cold” AND “immunodeficiency.”
Figure 1 shows the study selection process.
Table 3 summarizes the studies presented in the narrative review.
3.3.1. First Barrier: Physical Barrier
1 study was focused only on the physical barriers  and the aim of this study was to measure changes in the radical-scavenging activity of human physical barriers in vivo due to supplementation with different doses of vitamin C (100 or 180 mg) and at different time points. The study shows that orally administered vitamin C can have a significant radical-scavenging effect on physical barriers.
3.3.2. Second Barrier: Cellular Natural Immunity
Specifically, Schertling et al., 1990  used a high dose of ascorbic acid (5 g/die) and observed that additional administration of ascorbic acid and over a longer period of time may be expected to provide a therapeutic effect in the presence of increased activity of the pulmonary inflammatory cells (e.g., alveolar macrophages, granulocytes) with bronchial asthma. Harper et al., 2002, have selected, as an outcome, the reduction in spontaneous generation of superoxide and total antioxidant capacity observing reduced neutrophil generation of superoxide . In the study of Du et al., 2003, two different doses (10 g/day or 1 g/day) have been used in patients with pancreatitis and have demonstrated therapeutic efficacy . The potential mechanisms include promotion of antioxidizing ability of pancreatitis patients, blocking of lipid peroxidation in the plasma, and improvement in cellular immune function. Vojdani et al., 2000, using three different doses of ascorbic acid (500, 1000, or 5000 mg), did not observe adverse effects on the activity of NK cells even at high doses (5000 mg) . In four studies an improvement in the innate immune function was not observed [88–91]. Nieman et al., 2002, used a dose of 1500 mg and focused on immune changes after an ultramarathon, showing that supplementation of vitamin C does not serve as a countermeasure to postoxidative race and immune changes in carbohydrate fed ultramarathon runners . Davison and Gleeson  used a dose of 1000 mg, and the aim of study was to determine the effect of 2 weeks of supplementation with vitamin C on cortisol, adrenocorticotrophic hormone, interleukin-6, oxidative stress, and neutrophil responses to a single bout of endurance exercise. The authors concluded that supplementation with vitamin C for a maximum period of two weeks provides very limited or no protection against depression neutrophil function that is typically seen after prolonged exercise. The study of Hunter et al., 2012,  aimed to assess whether regular consumption of gold kiwifruit reduces upper respiratory tract infections (URTI) symptoms in older people and determined the effect it has on plasma antioxidants and markers of oxidative stress, inflammation, and immune function. The results showed that no changes to innate immune function (natural killer cell activity, phagocytosis) or inflammation markers (high-sensitivity C-reactive protein, homocysteine) were detected. The results of the pilot study of McComsey et al., 2003, conducted in HIV-infected subjects with lipoatrophy demonstrated that antioxidant supplementation did not change significantly immunity .
3.3.3. Third Barrier: Adaptive Immunity
Only one study in allergic adults was focused on the acquired immunity  and used a dose of 1500 mg; the aim was to determine the effects of dietary antioxidants on allergen-specific immune responses in sensitized individuals. The study found that antioxidant supplementation resulted in significant increases in serum levels of vitamin C, vitamin E, β-carotene, and selenium levels, compared with the placebo group, but here there was no change in serum antioxidative capacity (AC), plasma F2-isoprostanes, exhaled nitric oxide (eNO), or immune responses following supplementation with antioxidants compared with placebo.
Penn et al., 1991, have used a dose of 100 mg by observing an improvement in the immune function cell-mediated immunity, in particular T lymphocyte .
3.3.4. Vitamin C and Common Colds
The Cochrane review by Hemila et al., 2011, encompassing twenty-nine trials with 11,306 research participants, concluded that regular ingestion of vitamin C had no effect on common cold incidence in the ordinary population . However, it had a modest but consistent effect in reducing the duration and severity of common cold symptoms: in adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%); moreover, in children, 1 to 2 g/day vitamin C shortened colds by 18%. Maggini et al., 2012, used a dosage of 1000 mg plus 10 mg zinc and showed that supplementation with vitamin C and zinc may represent an efficacious measure, with a good safety profile, to help ameliorate the symptoms of this infectious viral disease .
A particular category of subjects that may need vitamin C supplements is athletes who engage in heavy physical activity, as these athletes’ vitamin C status may be depleted. A review demonstrated that in trials with participants exposed to short periods of extreme physical stress (including marathon runners and skiers), supplementation with vitamin C (0.6–1.0 g/day) halved the common cold risk ; the results of this review suggest that vitamin C supplementation may be beneficial for some of the subjects doing heavy exercise who have problems with frequent upper respiratory infections. An important point to consider is that overdosing vitamin C might be negative for immune defense as it inhibits oxidative processes that are needed for first line defense against bacteria or viruses [94–96].
In conclusion, regular supplementation (1 to 2 g/day) has shown that vitamin C may reduce the duration (in adults by 8%, in children by 14%) and the severity of CC. Therefore, given the low cost and safety, it may be also worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them, considering that under certain conditions vitamin C can act as a prooxidant, potentially contributing to oxidative damage.
3.4. Echinacea and Three Main Immune Interactive Clusters (Physical Barriers, Innate and Adaptive Immunity) Involved during an Episode of Common Colds
This research has been carried out based on the following keywords: “Echinacea” AND “immune response” OR “innate immunity” OR “adaptive immunity” OR “respiratory tract infections” OR “common cold” OR “immunodeficiency.”
3.4.1. First Barrier: Physical Barrier
Echinacea extracts have the immunomodulatory potency to promote both phenotypic and functional maturation of murine dendritic cells via modulating the activation of JNK, p38-MAPK, and NF-κB pathways . A similar effect has been demonstrated in human dendritic cells .
3.4.2. Second Barrier: Cellular Natural Immunity
Echinacea significantly normalized the restraint stress-induced reduction in splenocyte proliferation and splenic natural killer (NK) cell activity in rats . E. purpurea extract reduced the risk of respiratory complications by preventing virus-induced bacterial adhesion because it significantly reduced the expression of ICAM-1, fibronectin, and platelet activating factor receptor (PAFr) and consequently the adhesion of both bacterial strains . E. purpurea extract reduced the risk of respiratory complications through the inhibition of inflammation superstimulation (cytokine storms) by suppressing the expression of NFkB and possibly TLR-4 . Moreover, in animal models, Echinacea restored serum cytokine levels, including interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-17 (IL-17), as well as the mRNA expressions of these cytokines in the spleen . This immunomodulatory effect of Echinacea has also been confirmed in a pilot study in healthy subjects considering the expression levels of the cytokines IL-2, IL-8, IL-6, and TNF- alfa in lymphomonocytes and in plasma samples measuring the mRNA and protein levels .
3.4.3. Third Barrier: Adaptive Immunity
Echinacea treatment significantly increased the percentages of CD4+ and CD8+ T lymphocytes in the blood of rats . Moreover, water-soluble extract from Echinacea purpurea (L.) Moench has dose-related adjuvant effects on human T cell cytokine responses characterized by enhancing and suppressive effects that are regulated by T cell density . The mechanism of action involved modulatory effects indicating a possible role for water-soluble extract from Echinacea purpurea (L.) Moench (EchNWA) in enhanced Ca2+ mobilization and T cell activation. The authors underline that only the polysaccharide fraction was responsible for the immune modulatory effects described.
3.4.4. Echinacea and Common Colds
A double-blind, randomized, placebo-controlled trial demonstrated that the combination of Echinacea purpurea, zinc, selenium, and vitamin C may alleviate exacerbation symptoms in 108 chronic-obstructive pulmonary disease (COPD) patients with acute upper respiratory tract infections (URTI) . Echinacea also seems to have the same synergistic effect in combination with Justicia adhatoda and Eleutherococcus senticosus, as demonstrated in a parallel-group, randomized, double-blinded, placebo-controlled trial, in which this combination of extracts exerted significant antitussive effects in acute upper respiratory tract infections (URI) .
Regarding RCT with Echinacea supplementation alone, various studies demonstrated that use of this plant may be a complementary treatment of respiratory tract infections. In a randomized, double-blind, placebo-controlled trial, Echinacea reduced the total number of cold episodes, cumulated episode days within the group, and pain-killer medicated episodes; inhibited virally confirmed colds; and especially prevented enveloped virus infections. It showed maximal effects on recurrent infections, and preventive effects increased with therapy compliance and adherence to the protocol . The authors suggest a prophylactic intake of E. purpurea over 4 months to provide a positive risk to benefit ratio . In 2012, a study demonstrated that a highly standardized extract from roots of Echinacea angustifolia with a specific phytochemical profile (presence of the complex polysaccharide IDN5405, the phenylethanoid echinacoside, and substantial lack of alkamides) could enhance the immune response subsequent to the influenza vaccination . Another randomized, double-blind, double-dummy, multicenter, controlled clinical trial compared a new Echinacea formulation with a neuraminidase inhibitor, the gold standard treatment for influenza, and demonstrated the same effect . The same authors explain other possible benefits of this natural treatment, such as lack of induction of drug resistance and complications . A recent meta-analysis of randomized controlled trials indicated that Echinacea lowers the risk of recurrences and development of complications of respiratory tract infection, through antiviral and anti-inflammatory effects and the modulation of immune system . However, in 2014 a Cochrane review on Echinacea for preventing and treating the common cold was published, demonstrating that results of individual prophylaxis trials consistently show positive (if nonsignificant) trends .
In conclusion, the use of this plant represents a complementary treatment of respiratory tract infections. Prophylactic treatment with Echinacea extracts (2400 mg/day for prevention and 4000 mg/day during acute stages of colds) over 4 months appeared to be beneficial for preventing/treating CC.
In European populations, adults have between 2 and 5 infections annually and children typically present 6 to 12 “colds” per year, and rates of symptomatic infections increase in the elderly . Maintaining the immune defense system within a normal healthy state lowers the incidence of infection and/or lessens the severity of symptoms and/or shortens the duration of common colds. The immune system is an intricate network of specialized tissues, organs, cells, and chemicals protecting the host from infectious agents and other noxious insults. Although these defense mechanisms against invaders are very complex, they can be described as being organized in three main interactive clusters: physical barriers, and innate and adaptive immunity [9, 10]. The intakes of some nutrients and botanicals can significantly influence several components of immunity . There are three nutrients that have specific EFSA scientific opinion on the substantiation of health claims related to vitamin D , vitamin C , zinc , and normal function of the immune system. Moreover, there is EFSA scientific opinion on the substantiation of health claims related to zinc  and to vitamin C  and maintenance of normal physical barriers, that is, the first immune system barriers. Finally, for vitamin C  and Echinacea , there are Cochrane reviews regarding the use of these two nutrients for preventing and treating the common cold.
Therefore, vitamin D, vitamin C, zinc, and Echinacea have pivotal roles of three main immunoreactive clusters (physical barriers, innate and adaptive immunity) in terms of prevention and treatment (shortening the duration and/or lessening the severity of symptoms) of common colds. The present narrative review demonstrated that current evidence of efficacy for zinc, vitamins D and C, and Echinacea is quite strong that CC patients may be encouraged to try them for preventing/treating their colds.
Regarding vitamin C, regular supplementation (1 to 2 g/day) has shown that vitamin C may reduce the duration (in adults by 8%, in children by 14%) and the severity of CC.
Considering zinc, supplementation may shorten the duration of colds by approximately 33%. CC patients may be instructed to try zinc within 24 hours of onset of symptoms.
Regarding vitamin D, the supplementation protected against CC overall. Baseline levels and age need to be considered. Patients who were deficient in vitamin D and those not receiving bolus doses experienced the most benefit.
As for Echinacea, the use of this plant represents a complementary treatment of respiratory tract infections. Prophylactic treatment with Echinacea extracts (2400 mg/day for prevention and 4000 mg/day during acute stages of colds) over 4 months appeared to be beneficial for preventing/treating CC.
Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this article.
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