Vitamin D deficiency is a major public health problem worldwide in all age groups. It is prevalent even in those residing in countries with low latitude where it is generally assumed that ultraviolet (UV) radiation is adequate enough to prevent this deficiency. Vitamin D is a nutrient our body needs for building and maintaining healthy bones. That is because our body can only absorb calcium, the primary component of bone, when vitamin D is present. Vitamin D, a fat soluble vitamin and a secosteroid (pro)-hormone, has been traditionally considered as a key regulator of bone metabolism, and calcium and phosphorous homeostasis. Vitamin D plays a vital role in bone health and, along with calcium, helps prevent people from developing osteoporosis. Vitamin D also regulates many other cellular functions in our body. Its anti-inflammatory, antioxidant and neuro-protective properties support immune health, muscle function and brain cell activity. And there is growing evidence that it helps keep the immune system running properly. Though adequate sunshine exists, in Fiji, about 75 per cent of patients tested at OHPL were found to have vitamin D deficiency.
Sources of Vitamin D
Vitamin D is not naturally found in many foods, but we can get it from fortified milk, fortified cereal, and fatty fish such as salmon, mackerel and sardines. Our body also makes Vitamin D when direct sunlight converts a chemical in our skin into an active form of the vitamin (calciferol). The amount of Vitamin D our skin makes depends on many factors, including the time of day, season, latitude and our skin pigmentation. Depending on where we live and our lifestyle, Vitamin D production might decrease or be completely absent during the winter months.
Risk factors for vitamin D deficiency
Gender: It has been reported that women are more likely to develop vitamin D deficiency compared to men. Sunlight exposure, latitude and seasonal variations: Vitamin D concentrations are directly associated with the exposure to solar ultraviolet B photons. Therefore, Vitamin D concentrations tend to be lower during the winter season and for higher degrees of latitude (e.g. above 35° North latitude, little or no Vitamin D can be produced from November to February). Sunscreen, while important to prevent skin cancer, also can decrease Vitamin D production. Dark skin pigmentation: Dark-skinned people present an increased risk of low Vitamin D concentrations compared to white-skinned people, independently of age. Basically, most of the Vitamin D is obtained from sunshine when we get exposed our skin to direct sun. The darker the colour of the skin, the more slowly Vitamin D will be produced by skin. There is a biological adaptive reason of being white; the white skin produces Vitamin D more quickly. The original human would have had dark coloured skin from Africa to protect from the sun, and when he migrated to the north, he needs to produce more Vitamin D more quickly in the faint northern sunlight, so that is why his skin went white. Apart from this, there seems to be no other biological advantage from being white. Diet: Not including food stuffs rich in vitamin D in diet will lead to its deficiency. Obesity: The sequestration of Vitamin D in body fat reduces its availability. Moreover, the existence of a relationship between Vitamin D, inflammation, and adipose tissue has been hypothesized. Impaired renal function: This leads to impairment of renin-angiotensin system resulting in Vitamin D deficiency. Interestingly, all these risk factors tend to become more and more frequent with increasing age, easily explaining why Vitamin D deficiency is a typical condition in the elderly. Moreover, the aging process itself predisposes to Vitamin D deficiency, especially because of the age-related skin structure modifications.
Vitamin D and Immunity: The Rationale
Vitamin D reduces the scope of the acquired immune response: Sometimes, when people have lung infections, there is a complication called adult respiratory distress syndrome (ARDS) which is because of over reaction of body’s immune system releasing different types of cytokines (chemical substances) that cause lung injury which is called “cytokine storm”. Vitamin D reduces the scope of acquired immune response and it stops this extreme immune response. So, in ARDS, the problem is actually caused by the body’s immune system over reacting rather than lung infection itself, and Vitamin D helps to reduce this complication. Vitamin D is essential for regeneration of the epithelial barrier: The inside of the respiratory tract is lined by a layer of cells known as respiratory epithelium. Intact and healthy epithelium is necessary to give adequate protection against various infections. And, Vitamin D promotes the health of this epithelium. Maturation of immune cells: Vitamin D is important for the maturation of immune cells – namely lymphocytes, neutrophils, monocytes and dentritic cells – which express Vitamin D receptors and all these immunological cells respond to Vitamin D. Therefore, Vitamin D deficiency would affect maturation of these immune cells and so their functions. Vitamin D promotes immune function:Vitamin D has an essential role in immunomodulation, meaning it can promote as well as drive immune response. Without Vitamin D, basic immunity would be defective and the immune mediated inflammatory response can go unchecked. Vitamin D is also necessary for innate and adaptive immune systems. Innate immunity is the immunity with which we were born, that works against a wide variety of potentially affecting disease-causing (pathogenic) microorganisms including viruses, and the innate immunity is non-specific.
Vitamin D and acute respiratory infections
Acute respiratory infections are a major cause of global morbidity and mortality, and in the US are responsible for 10 per cent emergency department visits. It caused more than 2.65 million deaths worldwide in 2013 and Vitamin D can reduce it by 70 per cent in the risk group. Vitamin D stimulates immunity to viral and bacterial infections making this respiratory infections less likely to occur. There are evidence based studies that Vitamin D reduces the probability of contracting respiratory tract infections both bacterial and viral in origin. Vitamin D has been shown to be effective against viral respiratory tract infections such as respiratory syncytial virus (RSV), influenza virus and rhinovirus. Vitamin D supplement for the vast majority of people reduced the likelihood of getting respiratory tract infections as well as severity. Vitamin D deficiency has been linked to increased severity of both viral and bacterial infections. Systematic review and meta-analysis of individual participant data and observational studies show associations between low serum 25-hydroxyvitamin D (the major circulating Vitamin D metabolite) and susceptibility to acute respiratory tract infections. If we have low Vitamin D, we are at a higher risk of contracting acute respiratory tract infections. Results in this study showed overall 12 per cent protective effect of Vitamin D supplementation as monthly bolus against acute respiratory tract infections – in other words, individuals that received Vitamin D supplement had 12 per cent less chest infection, both bacterial and viral. Benefit was greater in those receiving daily or weekly Vitamin D without additional bolus doses. If people taking Vitamin D everyday, get 19 per cent less respiratory bacterial and viral infections. Protective effects against acute respiratory tract infection was strongest in those with profound Vitamin D deficiency at baseline 25-hydroxy Vitamin D levels < 25 nmol/L. Once the Vitamin D deficiency got corrected, these people got 70 per cent less chest infections. Vitamin D supplementation was safe and it protected acute respiratory tract infection overall. Patients who were very Vitamin D deficient and those not receiving bolus doses experienced the most benefit from Vitamin D supplementation. These findings support the introduction of public health measures such as food fortification to improve Vitamin D status, particularly in settings where profound vitamin D deficiency is common.
The link between Vitamin D and SARS-Cov-2
In the past, coronaviruses and influenza viruses have exhibited very high seasonality, with outbreaks occurring preferentially during the winter. The COVID-19 pandemic is indeed more severe above winter latitudes of 20 degrees, while it remains until now less severe in the Southern hemisphere, with a much lower number of deaths. Preclinical research suggests that the SARS-Cov-2 virus enters cells via the angiotensin converting enzyme 2 (ACE2) receptor which is present in various cells of human organs. Coronavirus viral replication downregulates ACE2, thereby dysregulating the renin-angiotensin system (RAS) and leading to a cytokine (chemical substances) storm in the host, causing acute respiratory distress syndrome (ARDS). Research also shows that Vitamin D plays a role in balancing RAS and in reducing lung damage. On the contrary, chronic Vitamin D deficiency induces fibrosis of the lungs through activation of RAS. Similarly, Vitamin D deficiency has been strongly associated in the literature with ARDS, as well as with a negative vital prognosis in resuscitation and with various comorbidities associated to deaths during SARSCov-2 infections. Conversely, Vitamin D supplementation has been reported to increase immunity and to reduce inflammatory responses and the risk of acute respiratory tract infections. New research suggests that hospitalised patients with COVID-19 and low Vitamin D levels could have a lower risk of dying or requiring mechanical ventilation if they receive Vitamin D supplementation. Earlier research has found that Vitamin D supplementation can prevent inflammation in other respiratory diseases, but the investigators noted that there have been limited studies examining the role of Vitamin D supplementation in COVID-19. A study published in the Journal of Clinical Endocrinology & Metabolism found that more than 80 per cent of 200 COVID-19 patients in a hospital in Spain had Vitamin D deficiency. Prompted by the evidence that people with Vitamin D deficiency are more likely to test positive for COVID-19 and experience significant symptoms, a team from the University of Chicago and Rush University is conducting two studies to learn whether taking a daily Vitamin D supplement can help prevent COVID- 19 or decrease the severity of its symptoms. Some of the studies reported that there is not enough data to recommend the use of Vitamin D to prevent infection with the virus that causes COVID-19 or to treat COVID-19. In addition, it is important to note that many reviews reported significant heterogeneity regarding the role of Vitamin D in preventing and treating SARS-Cov-2 infection, which may make the generalisability of the results difficult. This heterogeneity may be due to several reasons, including some publication bias, but also methodological issues, such as low numbers of trials, Vitamin D supplementation regime used and heterogeneity of participants’ characteristics.
Dose
1 mcg (microgram) = 40 IU
There are varying guidelines for how much Vitamin D adults should get on a daily basis, ranging from about 400 to 1000 international units (IU), according to the endocrine society. The guideline now is, all adults living in the UK should take a daily supplement containing 400 IU (10 mcg) of Vitamin D throughout the year (National Institute for Health and Care Excellence). This helps significant reduction in viral or bacterial respiratory tract infections. One review further showed that doses of 800 IU or less were protective of respiratory tract infections, but not higher doses. Two of the reviews also reported that the protective effect is observed only when single daily doses are used but not when bolus doses are given. With respect of Vitamin D supplementation regime, reviews showed that the size of the dose and the administration intervals might modify the effects of Vitamin D supplementation on respiratory tract infections. Daily smaller doses were more effective than single large boluses of Vitamin D. I wonder whether the same guideline applies to Fiji; however, in spite of good sunshine, at least 75 per cent of individuals tested at OHPL were found to have Vitamin D deficiency.
Safety
Vitamin D did not infl uence risk of serious adverse events of any cause. This is based on meta-analysis of over 10,000 patients. However, there are few recognised complications of excessive consumption of Vitamin D such as hypercalcaemia, a condition in which calcium builds up in the blood stream and causes nausea, vomiting, weakness and frequent urination, seen in 0.5 per cent in the experiment groups and kidney stones in 0.2 per cent. But, the incidence is the same in both groups, that is, group that received Vitamin D supplementation and group that received placebo. In this study, there was no signifi cant risk of adverse events with either bolus dosing or daily or weekly supplementation.
Conclusion
Vitamin D deficiency is a major public health problem worldwide in all age groups, and the prevalence of it is quite high in Fiji. It is really quite profound that Vitamin D supplement will reduce the likelihood of developing acute respiratory tract infections. In COVID-19 patients, low levels of Vitamin D is associated with increased mortality in hospitalised patients, increased ventilator requirement, higher SARS-Cov2 positive PCR (polymerase chain reaction) tests, elevated CRP (C-reactive protein), fi brinogen and D-Dimer levels and decreased clearance of SARSCov2. In addition, low levels of Vitamin D is associated with increased risk of developing or progressing to congestive heart failure, coronary artery disease, diabetes mellitus, hypertension and multiple sclerosis, and increased risk of any type of cancer and a decrease in survival rate. Though randomised trials yielded mixed results with signifi cant heterogeneity, many in the scientific community have argued that Vitamin D supplementation is generally safe and that any potential low toxicity would likely be strongly outweighed by any potential benefits in relation to protection from COVID-19. In the meantime, if you have a Vitamin D deficiency, talk to your doctor about whether a supplement might be right for you. If you are concerned about your Vitamin D level, ask your doctor about getting it checked.
- DR SIVASELVAM SIVAKUMAR is the laboratory head and consultant pathologist at Oceania Hospitals Pte Ltd. The views expressed are the author’s and do not reflect the views of this newspaper.
