75 articles indicate that Vitamin D should fight COVID-19 – Evidence Review Dec 10, 2020

Can Vitamin D Positively Impact COVID-19 Risk and Severity Among Older Adults: A Review of the Evidence

preprint DOI: 10.14302/issn.2474-7785.jarh-20-3650
Ray Marks1’ rm226 at columbia.edu
1Department of Health and Behavior Studies, Teachers College, Columbia University, New York, NY 10027, USA

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Table 1

Box I. Specific examples of how vitamin D supplementation may hypothetically promote immunity or more favourable Covid-19 outcomes among older adults who are vitamin D deficient or at risk for deficiency via its multiple gene regulating abilities [5].

• T regulatory lymphocytes can be increased or modulated by vitamin D [1, 34, 62]
• May help to reduce cytokine storm severity[1, 61, 62, 66]
• May reduce thrombocytic episodes and have a significant anticoagulation effect [1, 35]
• Has potential antiviral properties [36]
• May limit the expression of anti-oxidant genes [34]
• May potentially prevent or mitigate the complications associated with acute respiratory infections [37]
• Suppresses the actions of the renin-angiotensin system, which has a determining role in inducing inflammatory response related to Covid-19 [38]
• May help induce antimicrobial peptides, such as cathelicidine [24, 39, 40, 66]
• May help to induce innate immune responses or act as an immunosuppressant [39, 40, 62]
• May prevent exaggerated inflammatory responses and further damage to mucosal lung tissue in cases of virus-induced inflammation [26, 39]
• May protect against acute respiratory infections [42, 53] by helping to maintain the integrity of lung based epithelial tight junctions [34]
• May positively impact macrophage modulation and mucus secretion [34, 62]
• May help to prevent getting infected or ward off the infection without mortality [62]
• May reduce disease severity and need for intensive care [73]

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Background: The coronavirus Covid-19 strain that emerged in December 2019, continues to produce a widespread and seemingly intractable negative impact on health and longevity in all parts of the world, especially, among older adults, and those with chronic health conditions.

Aim: The first aim of this review article was to examine, summarize, synthesize, and report on the research base concerning the possible use of vitamin-D supplementation for reducing both Covid-19 risk and severity, especially among older adults at high risk for Covid-19 infections. A second was to provide directives for researchers or professionals who work or are likely to work in this realm in the future.

Methods: All English language relevant publications detailing the possible efficacy of vitamin D as an intervention strategy for minimizing Covid-19 infection risk published in 2020 were systematically sought. Key words used were: Vitamin D/ Covid-19, and Coronavirus. Databases used were PubMed, Scopus, and Web of Science. All relevant articles were carefully examined and those meeting the review criteria were carefully read, and described in narrative form.

Results: Collectively, these data reveal vitamin D is a powerful steroid like compound that is required by the body to help many life affirming physiological functions, including immune processes, but its deficiency may seriously impact the health status and well being of the older adult and others. Since vitamin D is not manufactured by the body directly, ensuring those who are deficient in vitamin D may prove a helpful overall preventive measure as well as a helpful treatment measure among older adults at high risk for severe Covid-19 disease outcomes.

Conclusions: Older individuals with chronic health conditions, as well as healthy older adults at risk for vitamin D deficiency are likely to benefit physically as well as mentally, from efforts to foster adequate vitamin D levels. Geriatric clinicians can expect this form of intervention to reduce infection severity in the presence of Covid-19 infection, regardless of health status, and subject to careful study, researchers can make a highly notable impact in this regard.

Introduction
The COVID-19 or pandemic remains an intractable problem despite months of study and investigation of the many possible causes, as well as strategies for amelioration or prevention. At the same time, adults with a variety of chronic health conditions may not be able to either access or receive optimal care due to many travel and other social restrictions. This narrative report focuses on vitamin D as a possible antidote to the widespread risk of severe illness on acquiring this virus, as well as for mediating its severity, and fostering a more rapid return to health. Since vitamin D may prove helpful for ameliorating or preventing Covid-19, and sunlight is one source of vitamin D that may be challenging to harness by many who are home bound or live in northern countries, or who are bound by a variety of cultural norms, work situations indoors or underground, or living in regions where the potency of ultraviolet light is diminished as a result of global warming, can a case be made for vitamin D supplementation among older at risk adults and others? Indeed, older adults, especially those who now have restrictions placed on their movements due to the Covid-19 pandemic may not only be highly vulnerable to the consequences of vitamin D deficiency, but may not understand the implications of their situation in this respect, even if they personally follow legal Covid-19 rulings in all respects.

Discussed is the evidence base in favor of efforts to ensure all citizens, including older adults, and especially those with chronic health conditions associated with a deficiency of vitamin D, such as diabetes, one of four main disease correlates found among Covid-19 cases. Some information on the past use of vitamin D in other infectious diseases such as influenza is discussed as well.

Drawn largely from the PUBMED database, the overview should provide the interested reader a general view of past work as well as current trends in this regard that might be worthy of further consideration and study, as well as applications in the health care field.

Covid-19, which may occur independently as a separate health condition, or in conjunction with one or more chronic health conditions, may well be life threatening, and even if not, may induce the presence of other illnesses, while heightening prevailing adverse life events and functional losses, including immense life quality and socioeconomic losses. While the world waits for a possible Covid-19 antidote, other remedies to offset excess risk of Covid-19 and its consequences must be sought as argued by Simonson [1]. In this regard, mounting evidence points to a possible role for vitamin D in explaining infection risk, as well possible benefits of intervening in this regard to offset or minimize this risk.

Although research in this realm is clearly in its infancy, and based largely on observational studies, Covid-19 infection and death rates do appear to be notably higher in the elderly than any other sub group, and this may be mediated in part, by the presence of a prevailing vitamin D deficiency. Since many adults suffer from this particular deficiency, it can be argued that a proportion of Covid-19 cases may be preventable. Since vitamin D sources are several, potential efforts to attain adequate sunlight exposure, exposure to foods or beverages containing vitamin D, and/or supplementation of vitamin D in vulnerable adults may be more beneficial than not.

Indeed, if found to be influential in any way, intervention in this regard may provide one avenue that is reasonably practical for purposes of securing the wellbeing of the aging person, especially in the case of the chronically ill older adult that alone can heighten risk of infection due to its overall potentially debilitating effect on immune, musculoskeletal and cognitive health. Others may be given medications that render them more prone to Covid-19, and less likely to be ‘good' surgical candidates or ventilator candidates if they have severe disabling chronic health conditions, especially those who may also be vitamin D deficient.

This work is significant because the ability to minimize Covid-19 risk and severity is currently of the highest importance, especially among the elderly confined to their homes in isolation, as well as nursing homes, or to situations that limit sunlight and nutrient based vitamin D exposure. As discussed by Mok et al. [2], the Covid-19 pandemic proceeds unabated, despite considerable public health efforts to mitigate this spread. The development of a vaccine is still awaiting confirmation, and even then vaccinations may be only part of the solution. However, other compounds with antiviral properties may be helpful to consider not only in the interim, but in the future.

Aims
This narrative review aimed to specifically examine the value of vitamin D therapy for or minimizing the risk of acquiring Covid-19 infections in the older population, especially those with preexisting vitamin D deficits. Its second aim was to offer recommendations for future consideration by clinicians and researchers in the field based on these findings.

Materials and Methods
To obtain the data for this review, the electronic data sources PUBMED, Scopus, and Web of Science were searched. The time period searched ranged from January 1 2020- December 2, 2020 and the key words included Covid-19, vitamin D/ coronavirus, older adults. All forms of study or analysis were deemed acceptable. However, because most empirical studies are in process, and unpublished, and no consistent intervention approach could be identified among these trials, a narrative summary of all available data including case studies, and uncontrolled observational studies was implemented. Selected material had to focus on vitamin D related facts relevant to infection risk and recovery, as well as symptoms of infection in the older adult. Excluded were articles that did not focus specifically on this set of issues and non English based articles. Preprints were used to highlight the possible scope and updated findings concerning this present topic, rather than for prescribing clinical guidelines.

Results
Of the more than 60,000 publications on Covid- 19, published as of December 2 2020, a total of 307 articles potentially relevant to the current topic were listed on PUBMED. Very few additional articles were found on the additional web sites. In terms of the topic of interest to this report, however, only 75 articles were deemed relevant as more publications than not did not meet criteria for this review, for example, they discussed vitamin D in children, or were letters to the editor. Even when the topic of the listed publication was relevant, it was clear that the prevailing reports were predominantly literature reviews, rather than actual studies. These were not uniform however, and tended to discuss studies with considerable variation in the samples studied, as well as types of vitamin D and modes of usage, with no consistency in reviewed content or overall approach. Most too, focused on the role of vitamin D as deduced from past studies on acute respiratory infections, or alternately on currently recorded medical records or observations on Covid-19 hospitalized cases made on a single occasion, rather than any observed prospective follow up studies. In particular, among the available publications related to Covid-19, and vitamin D the majority do not currently focus on vitamin D as a possible primary or secondary prevention approach. Indeed, very few have examined the possible role of vitamin D as an important biological determinant in mediating risk and outcomes of Covid-19 as experienced by older adults, even though vitamin D tends to meet Hill's criteria for infection causality as detailed by Annweiler et al. [3].

To provide an overview of this quite considerable, but potentially highly relevant material in this regard, this review chose to discuss the science base and basis as regards vitamin D as a form of possible form of prevention and/or therapy relative to acute respiratory infections, such as Covid-19 among older adults. Findings regarding its specific immune related benefits and others relevant to the safely and life quality of the older adult are described. The term vitamin D is applied throughout, even though several formulae and categories of this compound exist.

Prior Studies
Past research on the value of vitamin D in the context of health status, shows this compound in its various forms has the potential to strongly influence overall health status and outcomes across the lifespan, including the elderly, as well as outcomes of infections analogous to the Covid-19 pandemic. While most of these data point to research on vitamin D deficits and how these may raise the risk of more severe infection responses in the vulnerable adult [1, 4], other data show that there is a positive benefit of vitamin D supplementation on the risk of acute respiratory infection, depending on dosage. Simonson [1] also reports on the possible linkages of chronic health conditions, as well as Northern latitudes and cold weather that can implicate vitamin D deficits in exacerbating Covid-19 morbidity rates. The link between vitamin D and the immune system functioning has also been discussed [4].

Current Reports
Among the 75 studies and reports retrieved from the present search, Merzon et al. [5] who evaluated the degree of association between plasma vitamin D levels and the presence of Covid-19 disease and hospitalizations among 14,000 members of a Health Services unit found 10.1% to be Covid-19-positive. They also noted that the mean plasma vitamin D level among this infected group was significantly lower than that of the negative Covid-19 group. While the low vitamin D level may have been the caused by the Covid-19 presence, their univariate analysis demonstrated an association between low plasma vitamin D levels and the increased likelihood of acquiring a Covid-19 infection, followed by hospitalization due to this virus. In a multivariate analyses that controlled for demographic variables as well as psychiatric and somatic disorders, the adjusted odds of acquiring Covid-19 infections, as well as hospitalization due to the virus was unchanged, implying that a low vitamin D status is a possible risk factor for acquiring or exacerbating Covid-19 infection risk and severity.

Martineaus et al. [6] who assessed the overall effect of vitamin D supplementation on risk of acquiring an acute respiratory tract infection, associated with Covid-19 by reviewing data from several electronic data bases up until 2015 that were randomized, double blind, placebo controlled trials of vitamin D supplementation of any duration showed vitamin D administration was beneficial overall. That is, of the 25 eligible randomized controlled trials housing a total of 11321 participants up to 95 years of age, vitamin D supplementation appeared to reduce the risk of acute respiratory tract infection among all participants. In subgroup analysis, protective effects were also seen in those receiving daily or weekly vitamin D without additional bolus doses. It was concluded that vitamin D supplementation is able to safely protect against acute respiratory tract infection overall, and cases who are vitamin D deficient and receive non bolus supplements of vitamin D experience the most benefit.

Mok et al. [2] who examined a natural product library, among other sources in the search for Covid-19
prophylactic compounds, shortlisted the active form of vitamin D, termed calcitriol, as a prospective adjunctive agent in this regard. They then provided well documented background evidence that vitamin D has the potential to exhibit significant potent activity against Covid-19 or SARS-CoV-2. According to this group, their review findings pave the way for consideration of a practical host-directed therapy for helping to protect against SARS-CoV-2 or Covid-19 infection. Their arguments align to some degree at least with those of Mendy et al. [7] who sought to identify factors associated with hospitalization and disease severity in a racially and ethnically diverse cohort of COVID-19 patients and found that among the 689 Covid-19 patients in their study, a vitamin D deficiency was one factor associated with hospitalization and/or disease severity.
As well, Laird et al. [8] who specifically examined the role of vitamin D in the context of inflammation similarly support a strong plausible biological hypothesis and evolving epidemiological data as regards a favorable role for vitamin D in mitigating Covid-19 risk as proposed by Melzer et al. [9], especially in the case of any vitamin D deficiency. This is important to note, given that according to Zemb et al. [10] a vitamin D deficiency is easily modifiable, and daily vitamin D supplementation with moderate doses is safe and cheap. Moreover, even a small decrease in Covid-19 infections would easily justify this intervention even though disputed by Hastie et al. [11].
Ali et al. [12] further propose that since vitamin D is known to mitigate the scope of acquired immunity and to help regenerate endothelial lining damage, its thoughtful usage may be especially beneficial in minimizing the damage that often accompanies damage to alveolar structures in cases of acute respiratory diseases. These protective effects appear as well to increase up to 19% in those individuals subject to daily or weekly regimens of vitamin D compared to those dosing on a monthly bolus of vitamin D. Furthermore, there is a possible 70% chance of an effective protective outcome when a vitamin D deficiency is corrected by supplementation according to this group.
Radujkovic et al. [13] who studied 185 patients diagnosed with Covid-19 as regards vitamin D status at first presentation found 50% of these patients required hospitalization and a total of 22% were vitamin D deficient. When adjusted for age, gender, and comorbidities, this deficiency was associated with higher risk of severe illness and death, highlighting the need for interventional studies on vitamin D supplementation in this patient group.
According to Carpagnano et al. [14] who elected to examine the presence of vitamin D levels in 42 patients with acute respiratory failure due to Covid-19, 81% had hypovitaminosis D. As well their survival analysis showed that those patients with a severe vitamin D deficiency had a 50% chance of dying, while those with vitamin D levels > 10 ng/mL had a 5% chance of dying at 10 days.
Similarly Brenner et al. [15] who assessed the extent of vitamin D insufficiency and deficiency, and their association with mortality from respiratory diseases during 15 years of follow-up among 9548 adults ages 50-75 found high rates of vitamin D insufficiency and deficiency among this cohort. Compared to those with sufficient vitamin D, these aforementioned participants had increased respiratory mortality rates, hence, implying that vitamin D supplementation may be helpful in efforts to limit the immense burden of the Covid-19 pandemic.

State of Research
As noted above, the reports documented in this review, which are largely current, stem predominantly from either hypothetical, analogous research in the realm of respiratory conditions, anecdotal or observational data, hence should be viewed with caution, despite their overall meaningful conclusions in the face of a pandemic that has produced few preventive pharmacologic based strategies or amelioration approaches that are readily accessible and cost-effective. Indeed, as per Grant et al. [16] several observational studies and clinical trials do imply that vitamin D supplementation may be able to reduce the risk of influenza, even if this is not a consistent finding, and must thus be of sufficient current import to examine further [17]. As well, even though support for this idea may not be universal, the design and basis for the few available contrary studies has been questioned [17], thus these data too must be viewed cautiously to avoid discarding a potentially valuable adjunctive intervention, when in fact it may be helpful. Additionally, although several authors recommend that to reduce the risk of infection, very high vitamin D usage may be helpful to offset infection rates in vulnerable adults at risk for Covid-19, excess levels of vitamin D may prove more harmful than not, and should be studied carefully, before universally adopting its administration to the older severely affected adult with a Covid-19 infection.

On the other hand, as proposed by Caccialanza et al. [19] efforts towards ensuring safe efficacious vitmin D serum levels and methods of delivery should be examined carefully to establish if any of these can help to reduce the risk of respiratory failure requiring non-invasive ventilation or continuous positive airway pressure that limits food and beverage intake, and with this vitamin D analogs. According to Kakodkar et al. [20] there is also a need for assessing multiple parameters that influence and could influence the clinical course of Covid-19 infections and that may require optimization, as focusing on a single item may not prove efficacious in the long-term. However, as implied by D'Avolio et al. [21], moreover vitamin D concentrations in the plasma obtained from a cohort of patients in Switzerland did suggest vitamin D is one potentially important adjunct to bear in mind in the context of the Covid-19 fight' [22].

As well a careful review of allied past, as well as several existing studies (sampled in Table1), shows vitamin D deficits may predispose to infection of the lungs, and that the multiple mechanisms involved can be explained by vitamin D presence and extent of availability [4, 23]. Other data show, older adults who are affected most by Covid-19 are more likely than not to be vitamin D deficient, as well as experience the observed generally worse Covid-19 infection outcomes than younger patients. To the contrary, Ohaegbulam [25] found Covid-19 patients who received a high dose of vitamin D supplementation achieved more observable levels of vitamin D normalization, as well as improved clinical recovery rates. How the presence of lung disease and/or chronic smoke or pollution exposure can impact lung tissue vitamin D status and functioning, is not clear though, and

Table 1. Summary key study findings as of December 2, 2020 regarding the possible importance of efforts to identify vitamin D deficient older adults in the context of primary, secondary, and tertiary Covid-19 prevention approaches

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Many clinical trials are underway which are testing Vitamin D to fight COVID-19