Role of vitamin D supplementation in aging patients with COVID-19

Good nutrition and a healthy lifestyle strengthen the immune system. Currently, the world is facing the COVID-19 pandemic and this has once again highlighted the importance of nutrition, particularly vitamin D. Vitamin D is a unique micronutrient which plays a critical role in a host of physiologies, including proper functioning of the immune system and modulation of inflammatory responses. Evidence has shown that low vitamin D levels have associations with increased risk of COVID-19 infection; in fact, individuals deficient in vitamin D are reported to have a 54 % greater SARS-CoV-2 positivity rate [1]. It is well established that SARS-CoV-2 is more lethal in aged individuals [2,3] than in those with additional comorbidities and frailty [4,5]. Older adults in residential care have represented a disproportionately large proportion of infections and COVID-19 fatalities, for a number of reasons, including infectious outbreaks in facilities, significant comorbidity and poor health status. Additionally, vitamin D deficiency is very common among aged individuals. This is likely due to less sunlight exposure, decreased appetite and reduced vitamin D absorption in the gut. It is hypothesized that vitamin D supplementation may have a protective role in the prevention or treatment of COVID-19 infection in aging individuals.

1. Why does COVID-19 affect the aging population more severely?

The severity of COVID-19 is significantly greater in older adults (≥65 years), with this age group representing 80 % of hospitalizations and having a 23 times greater risk of death compared with younger individuals [6]. The control of viral load through effective immune response is a key indicator of COVID-19 symptom severity. The suppression and elimination of any virus, including SARS-CoV-2, requires key immune processes; however, in older people, many of these mechanisms are dysfunctional and increasingly heterogeneous, limiting immune efficacy in the face of infection [7,8]. However, it is still unclear exactly which specific aging mechanisms are principally associated with the progression of COVID-19. The immune system undergoes a range of changes with aging, including ‘immunosenescence’, that is, the decline of immunity [9], and ‘inflammaging’, a gradual elevation in systemic inflammation. However, in addition to the decline in immune function, vitamin D deficiency is also very common in the older population. Surveys in Europe on nutrition in older adults reported that 37 % of men and 45% of women had serum vitamin D concentrations < 30 nmol/L [[10], [11], [12]].

2. Role of vitamin D supplementation in aging individuals

According to the European Calcified Tissue Society Working Group, vitamin D deficiency is classified as 25(OH)D serum levels lower than 30 nmol/L. To achieve adequate serum vitamin D levels, higher doses of vitamin D supplements, such as 11,000 IU/day, can be taken for four weeks, while lower doses, typically 4,000 IU/day, require 12 weeks to achieve the same levels. On the other hand, others caution against doses of vitamin D greater than 4,000 IU/day and particularly very high doses of 10,000 IU/day, due to the potential for toxicity [13]. Generally, older adults are advised to have a balanced diet and healthy lifestyle with regular sun exposure alongside a supplement of 400–1000 IU/day in order to avoid deficiency [13,14]. Maintaining an optimal serum level of vitamin D is vital for adequate immune response, particularly in high-risk aging populations.

People with a low level of vitamin D have been shown to be 4.6 times more likely to be affected by COVID-19 than those with normal levels [15]. A study of 105 COVID-19 patients aged ≥65 years showed that older adults with vitamin D deficiency had a greater incidence of non-invasive ventilation support and were more likely to be admitted to a high-dependency unit; however, there was no change in mortality [16]. A study of 9,940 participants aged 50–75 found that vitamin D insufficiency or deficiency was statistically responsible for 41 % of all cases of respiratory disease mortality. The authors proposed that vitamin D3 supplementation could attenuate the burden of the COVID-19 pandemic [17]. Vitamin D supplementation boosts immunity and reduces the risk of COVID-19 infection, its severity and mortality [18,19].

In a quasi-experimental study, 77 older participants with COVID-19 were recruited and divided into three groups. Group 1 were those who received oral bolus doses of vitamin D3 (50,000 IU/month, or 80–100,000 every 2–3 months) prior to COVID-19 infection; Group 2 received 80,000 IU vitamin D3 immediately on COVID-19 diagnosis but had not received treatment previously; Group 3 were untreated controls. Group 1 reported a higher clinical response, with 93.1 % 14-day survival, compared with 81.2 % and 68.7 % in Group 2 and Group 3, respectively. This suggests that adequate vitamin D at the time of infection is associated with improved outcomes; however, immediate supplementation also decreased mortality [20]. Similarly, in a study of 66 participants aged 63–103 years, in a residential care facility, who received an 80,000 IU bolus of vitamin D3 on suspicion or diagnosis of COVID-19 or during the month prior, it was noted that vitamin D3 supplementation had an inverse relationship with the clinical improvement score in COVID-19 patients, and improved survival rates compared with those who did not receive supplements [21]. In a cohort study, 43 COVID-19 patients aged ≥50 were provided with dietary supplements consisting of 1000 IU vitamin D3, 150 mg magnesium and 500 μg vitamin B₁₂, which reduced the need for oxygen and intensive care support [22,23].

In order to reduce the spread of secondary infections, it is important to reduce the transfer of the virus among close household contacts. A pragmatic cluster-randomized trial evaluated the use of 3200 IU vitamin D3 daily in 1500 newly diagnosed COVID-19 patients. The vitamin D intervention decreased the rates of hospitalization and mortality while also proving to be beneficial in preventing infection among close household contacts [24].

While others have proposed that very large bolus doses of 300,000 IU of vitamin D could be beneficial in the prevention and treatment of COVID-19, there is no convincing evidence from randomized control trials to support this – particularly in light of increased risk of falls and toxicity with excessive doses [25]. While there remains much to be revealed regarding the impact of vitamin D in COVID-19, a number of ongoing clinical trials are exploring its use in managing and preventing SARS-CoV-2 infection (Table 1 ).

Table 1.

Registered clinical trials of vitamin D in aging patients with COVID-19.

Trial Number	Study design	Intervention	Condition or Disease	Age	Phase	Country	Primary outcomes Measure
NCT04351490 [26]	Randomized, Parallel Assignment, Open Label	2000 IU of 25-OH cholecalciferol and 30 mg Zinc gluconate for 2 months	SARS-CoV-2	≥ 60 Years (Older Adults)	Not Applicable	France	The survival rate in asymptomatic subjects
NCT04344041 [27]	Randomized, Parallel Assignment, Open Label	200,000 IU and 200,000 IU of cholecalciferol	SARS-CoV-2	≥ 65 Years (Older Adults)	Phase 3	France	Number of deaths during the 14 days
NCT04507867 [28]	Randomized, Sequential Assignment, Single (Investigator)	2000 IU of cholecalciferol and other nutritional support	SARS-CoV-2, Diabetes Mellitus, Hypertension, Obesity	30−75 Years (Adults, Older Adults)	Not Applicable	Mexico	Supportive care
NCT04751669 [29]	Double-blind, placebo-Controlled, Randomized Clinical Trial	10 μg of Cholecalciferol and various other nutrient supplements	SARS-CoV-2	18−80 Years (Adults, Older Adults)	Not Applicable	Spain	Need for hospital admission
NCT03188796 [30]	Randomized, Parallel Assignment	540,000 IU of vitamin D3 followed by 10 drops daily (4000 IU) for 90 days	SARS-CoV-2, Critical Illness, Vitamin D deficiency	18−100 Years (Adults, Older Adults)	Phase 3	Austria, Belgium	28-day mortality, length of stay at hospital
NCT04636086 [31]	Randomized, Parallel Assignment	25,000 IU/mL of cholecalciferol enterally	SARS-CoV-2	≥ 18 Years (Adults, Older Adults)	Phase 4	Belgium	Clinical improvement, length of stay at the hospital
NCT04386850 [32]	Multicenter Randomized, Double-Blinded, Placebo-Controlled Clinical Trial	25 μg of 25(OH)D3 for 2 months	SARS-CoV-2	18−75 years (Adults, Older Adults)	Phase 2 Phase 3	Iran	Disease severity, length of stay at the hospital

3. Recommendation

It is vital to maintain optimal vitamin D status, particularly in older adults, as it has beneficial effects across various body systems. Therefore, the following guidelines have been developed to protect musculoskeletal health, provide a proper immune response and minimize the risk of vitamin D deficiency. General recommendations for the aging population from the European Food Safety Agency are 800 IU/day vitamin D supplementation, while the UK Scientific Advisory Committee on Nutrition (SACN), US Institute of Medicine (IOM), and European Food Safety Agency recommend limiting intake to 4000 IU/day for adults. In addition to supplementation, exposure to sunlight for at least 13−15 min three times per week at noon is advised, to avoid deficiency. In the face of its well demonstrated beneficial effects outside COVID-19, and possible protective impacts in SARS-CoV-2 infection, vitamin D supplementation is likely a safe, cost-effective intervention that could decrease morbidity and mortality. Although evidence related to the effective dosage of vitamin D in COVID-19 is scarce, the recommended 800 IU/day is very likely to be safe and may be effective. Further randomized control trials are required in this area to validate the effectiveness of vitamin D supplementation in COVID-19 patients and establish a dose response. Nevertheless, preventative interventions to ensure adequate vitamin D status, particularly in vulnerable populations, is likely to improve COVID-19 outcomes.

Contributors

Hira Shakoor contributed to drafting of the editorial and to review and editing of the draft.

Jack Feehan contributed to drafting of the editorial and to review and editing of the draft.

Ayesha S. Al Dhaheri contributed to review and editing of the draft editorial.

Leila Cheikh Ismail contributed to review and editing of the draft editorial.

Habiba I. Ali contributed to review and editing of the draft editorial.

Salma Hashem Alhebsi contributed to review and editing of the draft editorial.

Vasso Apostolopoulos contributed to drafting of the editorial and to review and editing of the draft.

Lily Stojanovska contributed to drafting of the editorial and to review and editing of the draft.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

No funding was received for the preparation of this editorial.

Provenance and peer review

This article was commissioned and was not externally peer reviewed.