Inadequacy of Immune Health Nutrients: Intakes in US Adults, the 2005–2016 NHANES

4.1.1. Clinical Relevance

Maintaining adequate levels of vitamin D is important for optimal immune health. Low vitamin D status is a global public health problem in developed as well as developing countries, with approximately 1 billion people worldwide with deficient or insufficient levels of vitamin D [53]. Vitamin D does not occur naturally in many foods and people generally do not get enough sun exposure to produce adequate levels of vitamin D. Vitamin D status tends to be at its lowest in late winter and spring [54]. Declining levels of vitamin D may be linked to the seasonal prevalence of common viral infections. Accordingly, UVB exposure (representing vitamin D status) was negatively correlated with case fatality rates during the 1918–1919 influenza pandemic [54]. The “Spanish flu” pandemic killed more than 20 million people worldwide. Vitamin D activates the vitamin D receptor (VDR) to produce cathelicidin, which has antimicrobial activities in the lungs. An additional benefit of Vitamin D is reduced proinflammatory cytokine production, which may play a protective role during infections that cause a cytokine storm [54]. To avoid worsening of respiratory infections, Edlich et al. recommended that testing and treating vitamin D deficiency in health care providers and patients [55].

Coronaviruses are a family of viruses that can cause the common cold and upper respiratory infections, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [56]. Recent research suggests that vitamin D may influence the severity of infection of pathogenic coronaviruses that have emerged in the 21st century, such as severe acute respiratory syndrome-related coronavirus (SARS-CoV). The VDR is highly expressed in the lung and in vivo and animal research shows it may help prevent lung injury and pneumonia [57,58,59,60]. The SARS-CoV virus enters human cells via angiotensin-converting enzyme 2 (ACE2) [58]. In animal research, vitamin D-VDR signaling attenuated lung injury by blocking the renin–angiotensin system [59]. In an experimental interstitial pneumonitis mouse model, vitamin D3 led to supersession of lung inflammation and fibrosis markers [60]. Two reports assessed global data on persons with COVID-19 and found potential associations between low vitamin D status and increased risk of COVID-19 [61,62]. Vitamin D status has been shown to be significantly associated with severity of clinical outcomes in people with COVID-19. An analysis of 212 cases of people with COVID-19 found that those with vitamin D deficiency had a 19.61-fold higher risk of having a critical outcome compared to those with sufficient vitamin D blood levels (p < 0.001) [63]. It has been hypothesized that vitamin D supplementation reduces the risk of morbidity and mortality related to influenza and COVID-19. Grant et al. recommended raising 25(OH)D concentration above 40 ng/mL, which requires 5000–10,000 IU/day of vitamin D3 per day [64].

The Endocrine Society defines vitamin D deficiency as a serum level 25(OH)D of <20 ng/mL (50 nmol/L), vitamin D insufficiency at levels ranging from 21 to 29 ng/mL (52–72 nmol/L) and vitamin D sufficiency at levels > 30 ng/mL (75 nmol/L). A target level of 25(OH)D 40 ng/mL (100 nmol/L) ensures the individual’s “true” vitamin D value (ensures a 30 ng/mL due to lab variability) [65]. A large body of research has linked low vitamin D levels to respiratory disorders including influenza [23]. An analysis of NHANES demonstrated an increased prevalence of upper respiratory tract infection among individuals with deficient and insufficient status of vitamin D, when compared to those with sufficient levels [66]. The association is important given that analysis of 2001–2010 NHANES data showed that 29% of the US population is vitamin D deficient (<20 ng/mL) and an additional 41% are vitamin D insufficient (<30 ng/mL) [67]. In a prospective, observational study, it was seen that individuals with 25(OH)D levels at or above 38 ng/mL had a significant reduction in acute respiratory tract infections [68]. Furthermore, in a study looking at 25(OH)D levels in patients with community acquired pneumonia, 15% of the population with 25(OH)D levels < 12 ng/mL, indicating severe vitamin D deficiency, was associated with a higher 30-day mortality compared with patients with 25(OH)D levels > 12 ng/mL (p = 0.004) [30].

In two randomized controlled trials, vitamin D did not reduce the risk of upper respiratory tract infections. The VIDARIS randomized controlled trial found a monthly dose of 100,000 IUs of vitamin D3 for 18 months did not reduce the risk of upper respiratory tract infection over placebo. The average 25(OH)D level at baseline was 29 ng/mL, which is considered close to a sufficient level [69]. The vitamin D Outcomes and Interventions in Toddlers trial was conducted in children aged between 1 and 5 years [70]. The study found 2000 IU vitamin D per day did not reduce risk of respiratory tract infection over 400 IU per day. Respective mean baseline blood levels of vitamin D for the two groups were 35.9 and 36.9 ng/mL, which are sufficient blood levels of vitamin D. Participants in these trials had adequate vitamin D levels, so the applicability of these trials to broader US populations is unclear given the high prevalence of vitamin D insufficiency and deficiency. A broader approach using systematic review and meta-analysis has revealed potential benefits of vitamin D supplementation. Individual participant data from 25 randomized controlled trials involving 11,321 participants age 0 to 95 year examined the effects of vitamin D on acute respiratory tract infections [71]. They found that vitamin D supplementation significantly lowered risk for acute respiratory tract infections by 12%, however, there was a 70% lower risk of respiratory infection with vitamin D supplementation in participants whose baseline 25(OH)D levels were <10 ng/mL than in those with baseline 25(OH)D levels >10 ng/mL.

4.1.2. Current Findings

A large body of research shows a growing concern of the impact of inadequate intake of vitamin D and suboptimal/deficiency status on immune health. Our findings contribute to this concern of vitamin D inadequacy. Our data show that the percent of the population with intake below the EAR of 400 IU (10 μg) was 95% (food only) and 65% (food + supplement). Vitamin D usual intake was 188 IU (4.7 µg) (food only) and 556 IU (13.9 µg) (food + supplement) (Table S1). The RDA for vitamin D is 600–800 IU (15–20 μg)/day [72]. However, this recommendation is limited to bone health. The Endocrine Society recommends 1500–2000 IU (38–50 μg) to maintain a minimum of serum 25(OH)D concentration of 30 ng/mL [65]. For adults aged 19 years and older, higher doses (up to 10,000 IU/day), may be necessary to correct, treat, and prevent vitamin D deficiency [65].

4.2.1. Clinical Relevance

One of vitamin E’s most studied effects in immunity is prevention of immunosenescence seen with aging. In aging, there is a decline in T cell-mediated immunity caused by thymic involution, decreased naive T cells and decreased IL-2-simulated T cell proliferation capacity [39]. Vitamin E deficiency impairs immune function in both animal and human studies and the repletion of vitamin E is able to restore it [39].

Meydani et al. showed that giving 800 IU vitamin E/day for 1 month to healthy adults over 60 years of age had reduced levels of lipid peroxides and improved measures of immune function including, increased delayed-type hypersensitivity response and ex vivo T cell proliferation [33]. A follow-up trial showed that vitamin E (200 IU/day of dl-α-tocopherol) improved efficacy of hepatitis B and tetanus vaccines in older adults [77]. These results were confirmed in another study that showed 200 IU/day vitamin E also improved markers of both innate and adaptive immune function [18].

In several human clinical studies, Vitamin E supplementation has shown a clinical benefit in reducing respiratory infections in older adults. In older adults with pneumonia, those who received vitamin E supplements had an associated lower rate of self-reported rehospitalization [78]. In a randomized, double-blind, placebo-controlled trial, 600 nursing home residents (≥65 years old) who supplemented with 200 IU vitamin E/day (dl-α-tocopherol) vs. placebo reduced the incidence of upper respiratory infection by 20% [34]. In elderly adults, vitamin E supplementation did not impact self-reported respiratory infections, although participants with absence of respiratory infection were not confirmed, which may have resulted in reporting biases [22].

Although most clinical research on vitamin E shows an effective reduction in risk of viral infections of the upper respiratory tract (mostly the common cold), it may hold promise for a protective role against influenza viruses. Influenza viruses induce significant oxidative burst in the lungs, which can rapidly result in organ damage and impaired function [79]. Vitamin E is the most prevalent scavenger of lipid peroxyl radicals in the lipid membrane and quickly breaks peroxyl chain propagation reactions in vivo [79]. In animal studies, vitamin E was the most efficient antioxidant at reducing lipid peroxidation levels induced by influenza virus A infection [79]. More research is needed to understand the role of vitamin E in influenza virus infections.

It is estimated that ~34% of the US population has metabolic syndrome [80] and recent studies indicate vitamin E needs may be higher in people with metabolic syndrome [81]. Evidence also suggests that individual components of metabolic syndrome, such as obesity and diabetes are associated with higher mortality related to H1N1 influenza [82,83]. Recent data has suggested that diabetes, hypertension and cardiovascular disease worsens COVID-19 infections [84]. Since individuals with metabolic syndrome may be more vulnerable to infection-related severity and/or mortality, future research is needed to understand whether optimizing vitamin E intake levels can improve immune response, as seen in older populations.

4.2.2. Current Findings

Our data show that the percent of vitamin E intake below the EAR (18 IU/12 mg) was 84% (food only) and 60% (food + supplement). The prevalence of inadequacy of 84% has decreased from previous NHANES data that showed a 91% inadequacy [7]. Vitamin E usual intake was 9 mg (food only) and 28 mg (food + supplement) (Table S1). The RDA for vitamin E is 15 mg/day (22.4 IU) [85] and optimal daily intake for immune health for older adults is 134 mg/day (200 IU) [86]. Additionally, there is an emerging area of research around higher vitamin E needs in people with metabolic syndrome, who are at greater risk of infection [81].

4.3.1. Clinical Relevance

Several human studies have linked low plasma or serum vitamin A to impairment in immunity [89]. Most clinical studies on vitamin A have been limited to children with vitamin A deficiencies. Vitamin A deficiency is a global public health problem and increases risk of infectious diseases [89]. Vitamin A supplementation on a large scale in third-world countries is a cost-effective intervention to improve vitamin A status [91]. In a meta-analysis that included 43 randomized controlled trials studying children 6 months to 5 years of age found a 24% reduction in risk of all-cause mortality due to vitamin A supplementation. Measles morbidity was reduced by 50%. However, there was no impact on incidence of respiratory disease or hospitalizations due to diarrhea or pneumonia [92]. In HIV-infected adults, low vitamin A status has been associated with increases in disease progression and mortality, however results from studies are inconsistent [93].

4.3.2. Current Findings

Our data show that the percent of the population with intakes below the EAR (500–625 μg) for vitamin A was 45% (food only) and 35% (food + supplement). Vitamin A usual intake was 639 μg (food only) and 977 μg (food + supplement) (Table S1). The RDA for vitamin A is 700–900 μg/day [85].

4.4.1. Clinical Relevance

Extensive research has shown that vitamin C is a pivotal nutrient in immune health. Almost 150 animal studies have shown that vitamin C may alleviate or prevent bacterial or viral infections [94]. Numerous clinical trials have investigated Vitamin C supplementation for the prevention and treatment of the common cold with conflicting findings due to various study designs and differing doses. Very few studies on vitamin C and the common cold have measured vitamin C status. A study conducted on 28 healthy men between 18 and 35 years with plasma vitamin C < 45 µmol/L showed that 1000 mg vitamin C per day taken for eight weeks reduced duration of colds by 59% compared to placebo [95]. In 2013, a Cochrane review that included 24 trials found that vitamin C (at least 200 mg) did not significantly reduce the risk of common cold in the general population, but found a 52% reduction in cold in 5 trials with 598 marathon runners, skiers and soldiers engaged in subarctic exercises, indicating a higher need for those exposed to physical stress. In the general population, although there was no risk reduction in the common cold, at least 200 mg vitamin C reduced cold duration by 8% in adults and 14% in children. In children, 1 to 2 g/day vitamin C shortened colds by 18%. When taken after the onset of cold symptoms, vitamin C (1–8 g) did not affect cold duration or symptom severity [96].

Vitamin C may help prevent age-induced impairments of immune function. Preclinical researchers found high vitamin C intake in mice inhibited the age-related thymic involution and maintained T cell production, which is key to preventing the decline in T cell function commonly seen with age [36]. Low vitamin C status has been observed in the independent and institutionalized elderly population indicated by lowered plasma and leukocyte vitamin C concentrations. Low vitamin C plasma level concentrations (<17 µmol/L) in people aged 75–84 years was a predictor of all-cause mortality [97]. Research has shown vitamin C (500 mg–1 g) can improve vitamin C status and generation of ROS by neutrophils [27]. Clinical trials found vitamin C beneficial in patients with pneumonia with low vitamin C status. A randomized double-blind trial showed that vitamin C (200 mg) taken for 4 weeks in 57 elderly hospitalized pneumonia patients reduced the respiratory symptom score in those with low vitamin C levels [98]. Previous research in pneumonia patients showed that vitamin C (250 mg–800 mg/day) reduced days in hospital by 19%, whereas higher dosing of vitamin C (500 mg–1.6 g/day) reduced days in hospital by 36% compared to a placebo [94].

4.4.2. Current Findings

Our findings show that the percent of intake below the EAR (60–70 mg) for vitamin C was 46% (food only) and 33% (food + supplement). The prevalence of inadequacy of 46% is higher than previous NHANES data that showed a 37% inadequacy [7]. Vitamin C usual intake was 83 mg (food only) and 168 mg (food + supplement) (Table S1). The RDA for vitamin C is 75–90 mg/day [85]. Optimal daily intake is at least 200 mg/day, the amount to reach 60 μmol/L for optimal cell and tissue levels [99] and minimum dose found to decrease the duration of the common cold [96].

4.5.1. Clinical Relevance

The critical need for adequate zinc intake for maintaining the integrity of the immune system has been shown in animal and human studies. The impact of inadequate zinc intake on the immune system is rapid and extensive. Mouse models demonstrate that low zinc intake can lead to impaired immune function [20]. Zinc deficiency causes thymic involution, leading to reduced T cell production and an imbalance of T helper cells (Th2 > Th1) and an altered cytokine production which can lead to increased inflammation and oxidative stress. These changes mimic the changes seen in the aging immune system, so even marginal zinc intake in older adults may have a deleterious impact on immune health [24]. An earlier analysis found that 35–45% of US adults > 60 years had zinc intakes below the EAR [102]. Previous reports that plasma zinc concentration declines with age may be due to decreased absorption or uptake, or epigenetic alterations [24,38].

Several randomized controlled trials and meta-analyses have shown that 10–45 mg zinc/day improves several aspects of immune function in older adults. A randomized, double-blind, placebo-controlled trial showed 45 mg zinc (zinc gluconate) in forty people aged 56–83 years reduced IL-6, secretory phospholipase A, malondialdehyde and hydroxyalkyls, markers of inflammation and oxidative stress [103]. Another randomized, double-blind, placebo-controlled trial in 100 older adults (aged 50–70 years) with normal blood zinc concentrations gave 15–30 mg zinc supplementation for six months. Lower doses of zinc (15 mg zinc/day) significantly increased the proportion of helper T cells to that of cytotoxic T cells at six months [25]. Maintaining adequate zinc status may help prevent immune dysfunction in the older nursing home population. A one-year study of 420 nursing home patients found that participants with plasma concentrations of zinc >70 μg/dL had a lower risk of pneumonia [104]. Several clinical studies have shown zinc supplementation may reduce risk of common cold, although results are mixed. A recent meta-analysis of seven randomized trials with 575 participants with naturally acquired common colds concluded that zinc (zinc gluconate or zinc acetate, 80 to 92 mg per day) supplementation starting at the beginning of the first cold symptoms resulted in a 33% reduction in cold duration. Zinc acetate lozenges shortened colds by 40% and zinc gluconate by 28%. Zinc supplementation at 192–207 mg/day had a similar effect on cold duration [105]. Researchers are beginning to explore the effect of zinc on influenza virus. A recent in vitro study showed that zinc oxide had inhibitory effects on H1N1 influenza virus [106]. Future research is needed to extend these finding to in vivo models.

4.5.2. Current Findings

Our research shows, for all adults (≥19 years), the percent of intake below the EAR (6.8–9.4 mg) for zinc was 15% (food only) and 11% (food + supplement). The prevalence of inadequacy of 15% is slightly higher than previous NHANES data, which showed a 11% inadequacy [7]. Zinc usual intake was 12 mg (food only) and 16 mg (food + supplement) (Table S1). The RDA for vitamin zinc is 8–11 mg, which is adequate for healthy populations [107]. The optimal daily intake for immune health for older adults at high risk for infection has been suggested at 30 mg/day [16].