The Impact of Vitamin D on COVID-19

Importance of vitamin D

The recent worldwide outbreak of COVID-19 has left doctors and researchers searching for ways to boost our health, immunity and resilience. One method that shows potential focuses on increasing vitamin D levels. Vitamin D interacts with several different mechanisms involved in immune response and fighting off respiratory infection.

Vitamin D is not just a nutrient; it’s a hormone with receptors in nearly every cell and tissue of the body.[1] Vitamin D functions as both a genetic and  immune modulator, and has a systemic effect on overall health.[2] Research has correlated vitamin D levels with over 53 different disease states, including nine of the fourteen leading causes of death in the United States.[3] It is estimated that about 3% of the human genome is regulated by the vitamin D endocrine system and over 1000 genes in the human body are impacted.[4, 5] 

Seasonality 

Many diseases including influenza and past forms of coronavirus have shown winter seasonality.[7] Some researchers hypothesize that this seasonality is due to decreased sun exposure during the winter months.[8,9] In northern areas, between November and March, vitamin D cannot be produced from sun exposure. During these months the angle of the sun prevents the majority of UVB light from getting through the atmosphere, and therefore from reaching our skin to stimulate vitamin D production. As a result, our vitamin D levels noticeably decrease during the winter. 

The measure of vitamin D in the blood is often simply a biomarker for UVB sun exposure, so while researchers are trying to correlate vitamin D levels with various outcomes, they are often not considering other UV-related factors that could be relevant. The human body was designed to naturally create several beneficial hormones, including vitamin D, when our skin is exposed to UVB light. Oral vitamin D supplements are not processed the same way by the body and do not necessarily provide the same benefits. 

Early scientific reviews are emerging that suggest a correlation between COVID-19 and vitamin D deficiency. These studies show that northern latitudes and countries with higher rates of vitamin D deficiency, such as Italy, Spain, and Switzerland, are experiencing higher numbers of COVID-19 cases.[10, 33] Research from the Irish Longitudinal Study on Aging looking at COVID-19 related mortality by latitude found that countries below 35 degrees North have relatively low mortality, suggesting a possible role for vitamin D in determining COVID-19 outcomes. Another study that looked at the mean vitamin D level in 20 European countries concluded that vitamin D levels were strongly associated with the number of COVID-19 cases and mortalities.[12] While these types of findings require further review, this preliminary observational data indicates vitamin D may play a role in disease prevention and severity. 

Can vitamin D boost immunity against COVID-19?

Vitamin D enhances the innate immune response, the body’s non- specific, first line defense against foreign pathogens. Cathelicidins and defensins are peptides that have anti-microbial and immune modulating capabilities and act as anti-viral agents as part of the innate immune system.[14] Multiple studies have shown that vitamin D metabolites play a role in enhancing production of the human form of cathelicidins and defensins, thus enhancing innate immune response.[15] 

Vitamin D also enhances immunity by suppressing inflammation associated with both the innate and adaptive immune response.[17] In response to foreign pathogens, the immune system releases small proteins called cytokines, which trigger an immune response to help fight off the virus. Sometimes this response to infection goes into overdrive and excessive amounts of cytokines are released. This is known as a cytokine storm and can cause hyperinflammation. This inflammation damages organs throughout the body, leading to pulmonary infiltrates, lung injury, acute respiratory distress syndrome, disseminated intravascular coagulant, renal failure, and eventually death.[18] 

Clinical data from China reported that COVID-19 patients admitted to the intensive care unit showed high levels of cytokines, which suggests cytokine storms were present in severe COVID-19 cases.[19] Studies have found that vitamin D can suppress cytokine storms and it’s been hypothesized that this may help prevent severe cases of COVID-19.[20] Vitamin D decreases inflammation by suppressing the production of inflammatory cytokines and facilitating the production of anti- inflammatory cytokines.[21, 17] 

Vitamin D combats respiratory infections 

Many of those who die from coronavirus succumb due to complications related to acute respiratory distress syndrome (ARDS).[19] Shortness of breath, a deep cough, difficulties breathing, and chest tightness are all symptoms of COVID-19 that suggest the virus has infected the lungs and lower respiratory system. 

The lungs are made up of branching structures called bronchi, which divide into smaller and smaller bronchioles, which eventually end with microscopic air sacs called alveoli.In healthy lungs, oxygen crosses the alveoli into capillaries and is then carried around the body. When the body is infected with a respiratory virus, the immune system reacts by releasing inflammatory agents to kill infected cells. If this immune response is overactivated, the body starts to attack its own healthy cells as well as the virus cells. These dead cells build up and block oxygen exchange in the alveoli, leading to respiratory failure and critically low levels of oxygen in the blood. 

A large-scale study with almost 2,000 patients found that having low levels of vitamin D significantly increased risk of acute respiratory failure.[35] One study looking at patients with and at risk of ARDS found that vitamin D deficiency was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS.[22] Another study that investigated 476 patients found that 90% of patients with ARDS had low vitamin D levels and having low vitamin D was in turn associated with patients requiring a greater duration of time on ventilators.[23] 

A systematic review of 25 randomized controlled trials concluded that vitamin D supplementation significantly reduced the risk of acute respiratory tract infection.[24] 

Defense against coronavirus 

COVID-19, like other forms of the coronavirus, is a respiratory virus named for the crown like spikes on its surface. These spikes help the virus invade the respiratory system through interactions with protein receptors on the surface of cells. Once inside respiratory cells, the coronavirus takes over and creates copies of itself, which go on to invade other cells. Once COVID-19 infection spreads to the lower respiratory system it can cause cytokine storms, leading to hyperinflammation, severe lung damage, ARDS, and eventually death. 

Studies suggest that vitamin D could play a role in preventing cytokine storms and ARDS by regulating balance within the Renin-Angiotensin system (RAS).[26] Angiotensin II, the central biological effector in this system, is inflammatory and constricts blood vessels.[27] Uncontrolled levels of Angiotensin II causes inflammation and can lead to cytokine storms. High levels of circulating Angiotensin II have been found in patients with ARDS.[28] 

Angiotensin-converting enzyme 2 (ACE2) converts Angiotensin II into Angiotensin 1-7, which is not inflammatory. Capillary blood vessels in the lungs are one of the major sites of ACE2 expression and Angiotensin II production in the human body.[29] Research suggests that coronaviruses enter cells through ACE2 receptors, inactivating ACE2 and dysregulating the RAS.[30] By suppressing ACE2, coronaviruses lead to increased production of Angiotensin II and greater risk of cytokine storms and ARDS as a result. 

Vitamin D may be involved in the Renin-Angiotensin system through multiple different mechanisms. Vitamin D suppresses the gene that leads to the production of Renin. Renin is necessary for the production of Angiotensin II so by suppressing Renin production, vitamin D lowers the amount of Angiotensin II that can be produced and potentially prevents cytokine storms.[31] 

Vitamin D analogue, calcitriol, has also been found to increase the expression of ACE2.[36] ACE2 has been shown to have protective impact on the cardiovascular and respiratory system. A mouse model study found that ACE2 lessened the severity of acute lung damage caused by the influenza virus and that deficiency in ACE2 worsened severity of the disease.[32] Another study found that calcitriol exhibited a beneficial effect on acute lung injury in rats and reduced lung permeability damage.[26] 

Evidence suggests that vitamin D offers a promising, easily accessible way to support health and immunity. Vitamin D’s widespread impact on different systems in the body offers a multi-pronged approach for maintaining health. While more clinical trials are needed to determine if vitamin D could be effective for the prevention and treatment of COVID-19, studies show that vitamin D plays a role in supporting innate and adaptive immune response, decreasing the risk and severity of respiratory infections, and maintaining balance in the Renin- Angiotensin system.

Can vitamin D help with COVID-19?

Many studies are currently underway to help answer the question- “Does vitamin D help with reducing coronavirus risk or severity?”. Early correlational research strongly suggests a link between vitamin D and coronavirus outcomes. In one study, researchers found that patients over the age of 40 were 51.5 percent less likely to die from COVID-19 if they had a sufficient level of Vitamin D, which they define as being at least 30 ng/mL. Data was analyzed from 235 people who were admitted to the hospital with COVID-19. Only 9.7% of patients older than 40 years who were vitamin D sufficient succumbed to the infection compared to 20% who had a circulating level of 25(OH)D< 30 ng/ml. This study revealed an independent association between vitamin D sufficiency and decreased risk of adverse clinical outcomes from COVID-19. 

Read the full study.

Another study found that those who are vitamin D deficient have a 54% higher risk of contracting COVID-19 compared to people who are vitamin D sufficient. This study looked at data from more than 190,000 patients of all ages, ethnicities, and latitudes across the United States. The data showed that nearly 13% of those with lower-than-recommended levels of the nutrient tested positive for the coronavirus, compared to just over 8% of those with "adequate" vitamin D levels and 6% of those with high levels.

Read the full study.

One of the earliest pilot randomized clinical trials looking at the impact of vitamin D on COVID-19 found that high dose vitamin D significantly reduced the need for ICU treatment due to COVID-19. Of 50 patients treated with calcifediol (a form of vitamin D), one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50%). This suggests that vitamin D could reduce severity of COVID-19.

Read the full study.

A study of 185 patients diagnosed with COVID-19 found that vitamin D deficient patients had a higher hospitalization rate and required more intensive oxygen therapy and invasive mechanical ventilation. In these patients, vitamin D deficiency was associated with a 6-fold higher hazard of severe course of disease and about a 15-fold higher risk of death. This study demonstrates an association between vitamin D deficiency and severity/mortality of COVID-19, highlighting the need for interventional studies on vitamin D supplementation in COVID-19 patients.

Read the full study.

The use of advanced technology is giving additional insight into COVID-19 disease mechanism and potential treatment methods. One study used a supercomputer to analyze 40,000 genes from 17,000 genetic samples of COVID-19 patients in an effort to better understand the virus. Analysis of this data has lead to the development of a novel theory called the bradykinin hypothesis. The hypothesis provides a model that explains many aspects of Covid-19, suggests potential treatments, and explains why vitamin D may be useful for reducing the severity of the virus.

Read the full study.

Another study of 498 patients who had their vitamin D levels tested within a year of being tested for COVID-19 found that deficient vitamin D status was associated with increased COVID-19 risk. Patients who had vitamin D deficiency were almost twice as likely to test positive for the coronavirus than patients who had sufficient levels of the vitamin.

 Dr. David Meltzer, lead author of the study and chief of hospital medicine at the University of Chicago Medicine said, “Vitamin D is important to the function of the immune system and vitamin D supplements have previously been shown to lower the risk of viral respiratory tract infections. Our statistical analysis suggests this may be true for the COVID-19 infection.” 

Read the full study.