Will vitamin D become a new hope for the prevention and treatment of COVID-19?

The rapid spread of COVID-19 is a public health emergency that has attracted international attention. The clinical situation of COVID-19 is still not fully understood, but it is obviously related to respiratory symptoms, and in some cases it can induce acute multiple organ failure. Respiratory distress syndrome (ARDS), especially in elderly patients with a history of treatment for chronic diseases.
At present, not only need to develop vaccines to prevent infection, but also need more therapies to treat all COVID-19 patients, and take other interventions to reduce the risk of infection and its serious health consequences. The virus infects type II lung cells and intestinal epithelial cells as the main target cells. The spike protein of the virus binds to the angiotensin converting enzyme 2 on the cell surface to promote the virus to enter the target cells. ACE-2 is a regulator of the renin-angiotensin system and is distributed in many tissues of the human body, including the lungs, kidneys, gastrointestinal tract and cardiovascular system, which can explain the multiple organ failure of susceptible patients.
Researchers have proposed that vitamin D has a protective effect on COVID-19, and vitamin D has been shown to have immunomodulatory activity. Vitamin D interacts with receptors (VDR) in immune cells to regulate the innate and acquired immune system in response to the invasion of bacterial and viral pathogens. It also acts as a modulator of the renin-angiotensin pathway and down-regulates ACE-2.
COVID-19 is also spreading rapidly in Iran. An investigation by the COVID-19 Registration Center of Sina Hospital affiliated to Tehran Medical University in Iran found that the prevalence of vitamin D deficiency is higher, especially in the elderly, when exposed to SARS-COV-2 Later, the clinical manifestations became more serious. The researchers hypothesized that adequate vitamin D would reduce the risk of clinical severity and adverse clinical outcomes, including mortality associated with COVID-19 infection. Recently, medical records were analyzed in the inpatient database of the COVID-19 Registration Center of Sina Hospital affiliated to Tehran University of Medical Sciences in Iran, and it was found that appropriate vitamin D levels can reduce complications and deaths of COVID-19 patients, including cytokine storms (excessive Protein is released into the blood too fast) and eventually died of COVID-19. The study was published recently in “PLOS ONE”.

Will vitamin D become a new hope for the prevention and treatment of COVID-19?

01 data source

The infectious disease expert made the diagnosis based on the WHO’s interim guidelines and the recommendations of the Iranian National Committee for COVID-19. The patient is 18 years of age and older, with symptoms of acute respiratory infection (such as fever, cough, dyspnea) and no other clinical manifestations, the diagnosis is obtained by chest computer tomography (CT) scan results compatible with COVID-19 or through real-time Support for the definitive diagnosis of COVID-19 by polymerase chain reaction (RT-PCR).
Blood samples for measuring vitamin D status (measured serum 25-hydroxyvitamin D serum levels) were collected from 235 COVID-19 hospitalized patients, and the clinical outcomes of these patients were tracked. Inflammatory markers in the blood were also analyzed (C-reactive protein) and the number of lymphocytes, and then the researchers compared all these parameters in patients with vitamin D deficiency and those with adequate vitamin D.

02 The relationship between COVID clinical features and vitamin D

COVID-19 clinical outcome based on vitamin D status (left) Relative risk of COVID-19 clinical outcome related to patients with 25(OH)D<30 ng/mL (right) (source; PLOS ONE)
25(OH)D is the main form of vitamin D in the human body. The cut-off point of 25(OH)D equal to or higher than 30 ng/mL is used to define the adequacy of vitamin D. A total of 67.2% of patients 25( The OH)D level is less than 30ng/mL. In order to assess the role of vitamin D status in relation to the clinical characteristics of the disease, all data were divided into two subgroups based on 25(OH)D levels less than or equal to 30 ng/mL.
Vitamin D adequacy is associated with a statistically significant reduction in risk of loss of consciousness and hypoxia, the latter defined as arterial blood oxygen saturation below 90%. The percentage of serum CRP and lymphocytes in the blood of patients with sufficient vitamin D decreased and increased significantly. There were no significant differences between patients with and without vitamin D in terms of length of stay and ICU admission rate.

The scatter plot is related to the mortality of patients with serum 25(OH)D levels. Red dots represent patients who died, and black dots represent patients who survived. The solid black line separates patients with vitamin D deficiency/deficiency (below the solid line) from patients with sufficient vitamin D (above the solid line). Compared with the red dots below the solid line, the number of red dots (hospital mortality) above the solid line is significantly reduced; similarly, lowering serum 25(OH)D levels can continue to reduce hospital mortality. The dotted line indicates the serum level of 25(OH)D at 40ng/mL. In patients with a serum 25(OH)D of at least 40ng/mL (above the dotted line), mortality (red dot) is very rare.
After evaluating the mortality of the patient population, it was found that no one under the age of 40 died of COVID 19, but 16.3% of patients aged 40 and over died of infection. Among 206 patients over the age of 40, 20% had blood 25(OH)D<30 ng/mL, and 9.7% of patients who died had blood 25(OH)D at least 30 ng/mL (p = 0.04). In addition, only 6.3% of patients over the age of 40 died, and their 25(OH)D blood concentration was 40 ng/mL or higher.

03 Results and discussion

To assess the association between vitamin D adequacy and disease severity, all patients were classified according to the 30 ng/mL cut-off value of 25(OH)D according to the recommendations of the Endocrine Society. Data show that 25(OH)D levels of at least 30 ng/mL are associated with a significant reduction in the severity of clinical outcomes related to COVID-19 infection.
It is worth noting that the COVID-19 outbreak started in the winter of 2019. In 1981, someone proposed the “seasonal stimulation” hypothesis to explain the prevalence of influenza A around the winter solstice. The biology, physiology and epidemiology of vitamin D indicate that vitamin D may be a candidate for “seasonal stimulation” because the blood level of 25(OH)D is lowest at the end of winter.
The role of vitamin D in infectious diseases such as COVID-19 may be explained by its regulatory effect on acquired immunity and innate immunity. There are complex interactions between vitamin D, infection and the immune system. To help regulate innate immunity, macrophages stimulate toll-like receptors through the binding of infectious factors to produce 1,25(OH)2D. 1,25(OH)D binds to VDR in macrophages, thereby increasing the production of anti-viral antimicrobial peptides (AMPs) such as defensins. In the adaptive immune pathway, 1,25(OH)2D has more regulatory effects, and 1,25(OH)2D inhibits B cell activation and immunoglobulin synthesis. The hormone also promotes Treg cells, which are responsible for anti-infection effects by inducing IL-10 production. This result is very consistent with the immunomodulatory effect of vitamin D. This result shows that the percentage of lymphocytes in patients with vitamin D deficiency/insufficiency is lower than that in patients with adequate vitamin D.
The anti-inflammatory effect of 1,25(OH)2D can explain the protective effect of vitamin D on immune overreaction and cytokine storm in the subgroup of severe COVID-19 patients. This is also consistent with recent observations that C-reactive protein (CRP) is a substitute for vitamin D status and is related to the severity of COVID-19.
The researchers concluded that the higher CRP levels associated with vitamin D deficiency are associated with an increased risk of severe COVID-19. The CRP level of patients with high serum 25(OH)D levels is lower than that of patients with serum 25(OH)D<30 ng/mL, and the severity of COVID-19 infection in patients with sufficient vitamin D is lower than others Patients with higher 25(OH)D levels. This anti-inflammatory effect of vitamin D may prevent the cytokine storm in patients with COVID-19 and may explain the severity and risk of reduced mortality observed in patients with adequate vitamin D. Recent studies have shown that in the early stage of COVID-19, CRP levels are positively correlated with lung disease, which can reflect the severity of the disease. And before CT manifestations, the CRP level of severe COVID-19 patients increased significantly in the initial stage.
This study showed an independent association between adequate vitamin D [25(OH)D≥30 ng/mL] and reducing the risk of adverse clinical outcomes for COVID-19. Patients with adequate vitamin D have reduced the severity and mortality of the clinical outcome of COVID-19, and patients with adequate vitamin D also have significant differences in clinical characteristics. They are at lower risk of coma and hypoxia. Patients with sufficient vitamin D have significantly lower blood levels of the inflammatory marker CRP, while the total blood lymphocyte count is higher, indicating that adequate vitamin D can improve the immune function of these patients and increase inflammation markers. This beneficial effect on the immune system can also reduce the risk of acquiring this potentially life-threatening latent virus infection.
The researchers recommend further research, including RCT, to evaluate the role of vitamin D in reducing the complications and mortality of people infected with COVID-19. There is still controversy as to how the optimal serum level of 25(OH)D should play the best role. Researchers did observe that 6.3% of patients with 25(OH)D in their blood of at least 40 ng/mL died of infection, while 9.7% Of the patients and 20% of the dead have blood circulation levels higher or lower than 30 ng/mL. Therefore, for the immunomodulatory effects of vitamin D, a blood level of at least 40 ng/mL may be optimal. Medicilon, as a new drug development CRO, will continue to pay attention to research progress related to the treatment of COVID-19.

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