The role of vitamin D against COVID-19 infection,progression and severity

Abstract

BACKGROUND:

The number of coronavirus disease-19 (COVID-19) positive patients and fatalities keeps rising. It is important to recognize risk factors for severe outcomes. Evidence linking vitamin D deficiency and the severity of COVID-19 is tangential but substantial – relating to race, obesity, and institutionalization.

OBJECTIVE:

This study aims to examine the function of vitamin D and nutritional defense against infections such as COVID-19, which is the goal of this research.

METHODS:

This study includes observational cohort, cross-sectional, and case-control studies that estimated variances in serum levels of vitamin D among patients with mild or severe forms of COVID-19, and in patients who died or were discharged from hospitals. Studies that assessed the risk of developing severe disorder or death in patients with vitamin D deficiency, defined as levels of vitamin $D<$ 20 ng/mL, were also encompassed.

RESULTS:

In a retrospective study on 464,383 individuals, results showed that individuals who had the highest risks for severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, and for COVID-19 severity when infected, had vitamin D levels $<$ 30 nmol/L; Odds Ratio (OR) were 1.246 [95% Confidence Interval (CI): 1.210–1.304] and 1.513 [95%CI: 1.230–1.861], respectively. Additionally, in a retrospective observational study of 191,779 individuals in the USA. The SARS-CoV-2 positivity rate was greater in the 39,190 subjects with vitamin D $<$ 20 ng/mL [12.5%, 95% C.I. 12.2–12.8%] than in the 27,870 subjects with sufficient serum vitamin D levels [8.1%, 95% C.I. 7.8–8.4%] and in the 12,321 subjects with serum vitamin D $\geqslant$ 55 ng/mL [5.9%, 95% C.I. 5.5–6.4%].

CONCLUSION:

People hospitalized for COVID-19 should be checked for vitamin D status and supplemented, and high-dose-in testing should be considered in the recovery trial. More importantly, screening for malnutrition and the administration of the best nutritional supplements are essential for the immune system of the human body to function as it should be. Thus, nutritional supplementation is crucial for people with risk factors as well as older adults with compromised immune systems.

Keywords

Acute respiratory distress syndrome coronavirus diseases respiratory tract infection mitochondrial dysfunction antioxidants Vitamin D

1. Introduction

Figure 1.

Structure of SARS-CoV2 [1].

After activating the spike protein via transmembrane protease serine 2 (TMPRSS2), the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) binds to the angiotensin-converting enzyme 2 (ACE2) receptor. The RNA virus COVID-19 has spikes of glycoprotein on its surface. Its envelope, when seen under an electron microscope, resembles a typical crown as shown in Fig. 1. They are genetically characterized into four primary species: the $\alpha$ , $\beta$ , $\gamma$ , and $\delta$ . The former two species usually infect mammals, while the latter two mainly infect birds. The former two genera typically infect mammals, whereas the latter two predominantly infect birds [1]. Numerous factors, including sex, age, race, and causative comorbidities, can affect the severity of COVID-19. No recognized antiviral therapy exists for COVID-19, even though several curative medications have been proposed [2]. The clinical disorders ranging from asymptomatic or mildly symptomatic forms to acute respiratory failure needing mechanical ventilation and treatment in the critical care unit to multiorgan and systemic presentations like sepsis, COVID-19 spans a variety of clinical diseases: septic shock and numerous dysfunctional syndromes. Pneumonia, the most prevalent sign of infection, is manifested by coughing, fever, shortness of breath, and bilateral infiltrates on chest X-rays [3].

There are currently no precise clinical classifications to differentiate COVID-19 from other viral respiratory infections. Two different symptoms, sore throat and headache, are less frequent. Along with respiratory symptoms, digestive problems, including nausea and diarrhea, have also been noted; in some instances, they may even be the primary complaint. Asymptomatic carriers can potentially transfer the illness by respiratory droplet transmission when they come into contact with another individual [4].

2. Materials and methods

This study encompassed observational cohort, cross-sectional, and case-control studies that estimated serum levels of 25 hydroxy-cholecalciferol [25(OH)D] among patients with mild or severe forms of COVID-19. Studies that assessed the risk of emerging severe cases or death in patients with vitamin D deficiency, well-defined as levels of 25(OH)D lesser than 20 ng/mL, were also encompassed. Mechanisms of COVID-19, including particular mutations that affect mitochondria, the damage induced by viral infection to COVID-19, and the protective impact of vitamin D, have both been extensively covered in reviews and meta-analyses, which were included in this article.

2.1 Diagnosis of coronavirus disease

The following diagnostic techniques are used on patients with suspected infections to discover SARS-CoV-2 positive DNA in samples of sputum, respiratory tract secretions, throat swabs, and real-time reverse transcription polymerase chain reaction (RT-PCR). With COVID-19, the white blood cell count can change. Although leukopenia, leukocytosis, and lymphopenia have all been noted [5], lymphopenia seems to be more prevalent. Higher levels of aminotransferase have been linked to lower levels of lactate dehydrogenase, although higher levels of ferritin have not. At the time of admission, the serum procalcitonin levels of many pneumonia patients were normal. The level of lymphopenia severity and D-dimer concentrations have both been associated with mortality. A different research found that lower lobe involvement, circumferential distribution, and bilaterality are the most common characteristics of thoracic sectional abnormalities [6]. A chest CT scan may be helpful in categorizing a diagnosis, but no result can entirely or entirely exclude the likelihood of COVID-19. Despite the possibility of false positive results, the diagnosis of COVID-19 is typically supported by a positive SARS-CoV-2 test. RT-PCR identified the SARS-CoV-2 RNA. If initial tests are negative, but there is still a suspicion of COVID-19, the World Health Organization advises repeating sample collection and testing from numerous respiratory locations [7]. Serological testing should generally be able to classify people who have infection now or in the past but a negative PCR result once the results are available. Co-infection with SARS-CoV-2 and other respiratory viruses, such as influenza, has been observed to influence management evaluations [8].

The vulnerability to viral infection and the severity of disease following a viral infection are significantly influenced by host features that affect the immune response. Age and ethnicity, for instance, appear to have a significant impact on survival when patients contract the recently identified SARS-CoV-2 agent [9].

To avoid malnutrition, it is essential to consume the appropriate amounts of macronutrients for energy, protein, fat, and carbohydrates. Additionally, it’s necessary to have enough vitamins and minerals to prevent viral illness.

2.2 Mitochondrial dynamics and viral infection

Viral infection results in modifications that have various levels of impact on mitochondrial dynamics. Therefore, mitochondrial DNA is essential for the synthesis of the respiratory chain’s enzymes and the proper operation of the organelle. As a result, viruses destroy mitochondrial DNA to circumvent the immune system of the host cell [10].

In order to preserve cellular energy balance and ensure effective replication while avoiding a mitochondrial antiviral response, viruses change the majority of mitochondrial metabolic pathways [11]. Some viruses employ the lipids and nucleotides available for their replication to raise aerobic glycolysis and use glucose as an energy source so as to sustain fatty acids (FA) [12]. As found in measles virus infection in lung cancer cells, mitochondrial degradation of an antiviral signaling protein is another strategy for promoting fragmentation to postpone the antiviral immune response [13]. Unknown processes allow viruses to affect the innate immune system. A current study discovered that the open reading frame of the SARS-CoV-9b (ORF-9b) protein, which results in mitochondrial fusion, increases Drp1 degradation. Autophagy inhibition had no impact, whereas proteasome inhibition had an impact on this reduction. Additionally, lower mitochondrial antiviral protein signaling has been linked to decreased Drp1 expression [14]. Reactive oxygen species (ROS) are produced mainly by mitochondria in the cells. Preserving a balance between ROS generation and scavenging is necessary for optimum cell activity. Viral infection affects the mitochondrial production of ROS as viruses can mainly boost or inhibit a variety of mitochondrial processes in order to develop and produce offspring [15].

In general, viruses boost ROS production, which allows particular host cellular pathways to facilitate virus growth- reproduction. The biotransformer enzymes spermine oxidase, cytochrome P450, and xanthine oxidase may also create them when they come into touch with the host. According to some studies [16], viruses may use both an increase and a decrease in oxidative stress as a survival strategy. In addition, several viral infections restrict the activity of non-enzymatic antioxidants such as vitamin C, carotenoids, minerals, and cofactors, as well as essential antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase, and catalase. (CAT) because viral regulatory proteins affect cellular functions [17].

Figure 2.

Suggested mechanism of action and synthesis of catalase nanocapsules [18].

(A) The schematic illustrates that elevated ROS levels in COVID-19 patients lead to oxidative damage, viral replication, and a cytokine storm (B) The main method for reducing the formation of downstream ROS is by removing H₂O₂ from the reaction pathways (C) The CAT nanocapsules synthesis by the polymerization of 2-methacryloyloxyethyl phosphorylcholine and N,N’-methylenebisacrylamide around CAT molecules showing better stability and circulation half-life. It is the most abundant and active enzyme to break down H₂O₂. It is found in the liver, red cells, and the alveolar cells of the lung. It is capable to decompose 10⁷ molecules of H₂O₂ within a second as demonstrated in Fig. 2 [18].

2.3 The role of trace elements and vitamins in the immune system

Poor clinical outcomes after viral infection have been linked to low levels of selenium, zinc, and other micronutrients, as well as vitamins A, E, B₆, and B₁₂. In addition to vitamins A and D, vitamin B, vitamin C, omega-3 polyunsaturated fatty acids, and trace elements, i.e., selenium (Se), zinc (Zn), and iron (Fe) should be included when screening micronutrients in COVID-19 patients, according to previous study [19]. Age, smoking, obesity, and chronic conditions, i.e., diabetes mellitus (DM) and hypertension (HTN) are risk factors for vitamin D insufficiency [20].

3. Results

Numerous studies have linked vitamin D deficiency or insufficiency to a higher risk of COVID-19 severity and SARS-CoV-2 infection [21]. In a retrospective trial on 464,383 individuals, results showed that individuals who had the greatest risks for SARS-CoV-2 infection, and for COVID-19 severity after infected, had low vitamin D levels ( $<$ 30 nmol/L); Odds Ratio (OR) were 1.246 [95% Confidence Interval (CI): 1.210–1.304] and 1.513 [95%CI: 1.230–1.861], respectively [22]. Kaufman et al.’s retrospective study of 191,779 US individuals found that individuals with lower serum vitamin D levels were more likely to contract SARS-CoV-2. The SARS-CoV-2 positivity rate was greater in the 39,190 subjects with vitamin D deficiency ( $<$ 20 ng/mL) [12.5%, 95% C.I. 12.2–12.8%] than in the 27,870 subjects with adequate serum vitamin D levels (30–34 ng/mL) [8.1%, 95% C.I. 7.8–8.4%] and in the 12,321 subjects with serum vitamin D $\geqslant$ 55 ng/mL [5.9%, 95% C.I. 5.5–6.4%]. This association held true for individuals across geographical latitudes, ethnicities, age and sexes groups [23].

Figure 3.

Vitamin D metabolism [25].

Data from the National Health and Nutrition Examination Survey (NHANES) 2001–2006 [24] showed a negative association between 25(OH)D levels and acute infection of the respiratory system. Adults with a healthy level of 25(OH)D are less likely to develop acute respiratory tract infections, as depicted in Fig. 3 [25]. Studies have examined the relationship between COVID-19, and a lack of vitamin D. Since vitamin D can be created on the skin by exposure to sunlight, living at a higher altitude increases the chance of acquiring a vitamin D shortage [26]. The higher mortality in COVID-19 in Indonesia has also been linked to vitamin D insufficiency, which is defined as a level of 20 ng/mL or lower, and deficiency, which is distinct as a level of 21–29 ng/mL [27]. Vitamin D is a pro-hormone that can be consumed externally through food or supplements or generated by the skin [28].

Vitamin D must be obtained through oral ingestion, although UV radiation with a wavelength of between 290 and 315 nm is the predominant physiological source [29]. People with darker complexion or older bodies have less capacity to synthesize vitamin D. Although The majority of the conversion of 25(OH)D to 1,25-dihydroxy vitamin D [1,25(OH)₂D], which is the physiologically active metabolite, occurs in the kidney. Numerous other cells and tissues are known to be activated by vitamin D. They comprise cellular components of the innate and adaptive immune systems, emphasizing the importance of vitamin D as an immunological regulator [30].

The host variables that affect the immune response show a significant role in measuring a virus’s capacity to infect a host and cause illness. For instance, when patients have SARS-CoV-2 infection, demographic characteristics, including age and ethnicity, appear to have a significant impact on survival. Due to more severe disease, the mortality rate for persons over the age of 80 is 12.5%, compared to 0.01% for children under the age of 10. Obese patients have a mortality rate that is 50% higher than black patients [31]; mortality rates are twice as high as those of white patients [32]. Comorbid conditions like diabetes and high blood pressure (BP) are both common in obese and older people. It has also been proposed that dietary issues, exceptionally a particularly high incidence of vitamin D insufficiency in this population, may influence illness severity and infection risk by lowering immunity [33].

3.1 Vitamin D deficiency and inflammatory processes in severe COVID-19

Vitamin D deficiency may seem biologically conceivable for some SARSCoV-2-infected people’s illnesses to get worse. This is because COVID-19 and vitamin D deficiency both have different immune profiles and extra biochemical abnormalities. These include higher levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- $\alpha$ ), as well as a shift toward enhanced Th1 adaptive immune responses, ACE2 inhibition, and an improvement in coagulation [34]. Hypoxia inducible factor 1 (HIF-1) alpha and nuclear factor kappa B (NF- $\kappa$ B) are two examples of redox-sensitive transcription factors that may be stimulated by the oxidative environment caused by viral infection. The TNF induces the release of the cytoplasmic inhibitory protein inhibitor of nuclear factor kappa B (I $\kappa$ B $\alpha$ ), which in turn stimulates NF-B. To increase viral replication, this transcription factor stimulates the transcription of cellular and viral genes before translocating to binding to DNA and the nucleus [35].

Figure 4.

The interaction of vitamin D levels, RAAS overactivation, and mitochondrial dysfunction in the pathogenesis of COVID-19 [44].

Additionally, local hypoxia is brought on by viral infection because phagocytic cells produce more HIF-1, which activates crucial genes involved in autophagy through transcriptional regulation of the synthesis of HIF-1. Numerous studies have demonstrated that NF-B is one of the critical mediators linking natural immunity and the hypoxia response. These co-factors aid the hypothesis that low levels of vitamin D may worsen a “cytokine storm” and extra-related biochemical anomalies that are frequently detected in patients with severe COVID-19 [36].

3.2 Techniques to reduce viral infections and vitamin D

Reviews [37, 38] have described numerous ways in which vitamin D lessens the likelihood of microbiological illnesses. Vitamin D lowers the risk of viral infection and mortality through three different mechanisms: physical barrier, innate cellular immunity, and adaptive immunity [39]. One of these is preserving the connections between cells, gaps, junctions, etc. Others include enhancing cellular immunity by lowering cytokine storm while modifying interferon and TNF- $\alpha$ , managing adaptive immunity by stimulating T cells and inhibiting type I helper T cell responses, and more [40]. Additionally, vitamin D administration has been shown to increase the quantity of CD4+ T cells that are HIV-positive. Lymphopenia is one of the primary signs of an acute SARS-CoV-2 infection [41]. Vitamin D showed potential in lung tissue and protective properties against experimental interstitial pneumonia in murine models and human cell lines [42]. By boosting the presentation of antimicrobial peptides or by directly preventing viral multiplication in the respiratory tract, vitamin D has been shown in numerous in vitro investigations to play a significant role in local “respiratory homeostasis” [43]. Therefore, severe COVID-19 cases can be identified by acute respiratory distress syndrome and heart failure, and these diseases may be related to vitamin D deficiency. Vitamin D insufficiency has been associated with declined lung function and chronic cardiovascular disease (CVD) because it stimulates the renin-angiotensin-aldosterone system (RAAS) as illustrated in Fig. 4 [44].

Patients with such comorbidities report a greater frequency of severe disease in COVID-19, despite the immunological actions of vitamin D and its crucial role in maintaining immune homeostasis. The study requires randomized controlled trials to understand the potential role of vitamin D in preventing acute respiratory infections and in protecting immune responses against respiratory tract microorganisms [45].

3.3 Studies informed by vitamin D levels measured during COVID-19

The 1, 25(OH)₂D is existent in serum at deficient levels and has a short half-life. As a result, the majority of tests measure the blood’s 25(OH)D levels. This involves proteins in general, specifically albumin and the protein that binds vitamin D. This protein concentration tends to drop in disease as a detrimental response to the acute phase. This tends to reduce the production of 25(OH)D, which can then be absorbed by the immune system and epithelial cells, as well as the quantity of vitamin D already circulating in the blood. However, the fluctuations of serum 25(OH)D during disease are still obscure [46].

Table 1
Comorbidity prevalence among all patients, including those on ventilators or ICU

Country	Patients number	CVD (%)	HTN (%)	DM (%)	Obesity (%)	Ref
China	41	15 (23)	15 (15)	20 (8)	Not reported	14
China	138	14.5 (25.0)	31.2 (58.3)	10.1 (22.2)	Not reported	4
China	150	8.7 (19.1)^b	16.7 (17.6)^b	16.7 (17.6)^b	Not reported	11
China	191	8^a (24)^a,b	30 (48)^b	19 (31)^b	Not reported	33
Italy	1,591	NR (21)	NR (49)	NR (17)	Not reported	12
USA	393	13.7a (19.2)^a	50.1 (53.8)	25.2 (27.7)	35.8 (43.4)	31

Figure 5.

Infection with COVID-19 and concomitant effects of vitamin D insufficiency [56].

4. Discussion

In people with COVID-19 who do not have concurrent conditions, the reported death rate, including those on ventilators or intensive care units (ICU), is 1.4%. Still, it is more renowned than 8% of people with chronic respiratory illness, DM, high BP, and other CVDs, respectively [47] (Table 1).

Vitamin D directly disturbs smooth muscle cells, causing proliferation and subsequent CVD. In a meta-analysis with CVD as a risk factor, vitamin D concentration was recorded with hypertriglyceridemia, obesity, and DM [48].

The outcomes of a prospective nested case-control research also showed that, after controlling for several confounders, vitamin D insufficiency increased the risk of myocardial infarction in comparison to an average level of 25(OH)D. Vitamin D levels and the risk of CVD are linearly and negatively correlated, according to a meta-analysis of 19 studies [49].

A resistant HTN is a substantial CVD risk factor. Severe short-term or even long-term vitamin D deprivation can promote HTN via modulating the RAS [50]. Numerous cross-sectional investigations have shown a relationship between low vitamin D levels and elevated plasma renin activity, higher angiotensin II (Ang II) levels, and various Ang II reactions [51]. Oral vitamin D therapy has been proven to significantly decrease diastolic BP in people who have a history of CVD risk [52]. Vitamin D level is associated with the chance of developing DM, insulin resistance (IR), and other CVD risk factors. An observational study comprising 494 women who underwent repeated metabolic profiling discovered that parathyroid hormone overproduction and vitamin D deficiency were independently predictive of IR, hyperglycemia, and $\beta$ -cell dysregulation [53].

Through the pancreatic RAS, vitamin D insufficiency affects insulin synthesis, IR, and $\beta$ -cell malfunction. By increasing the synthesis of renin and Ang II, it can subsequently increase the production of ROS and the G protein RhoA. The obstruction of intracellular glucose transport routes fosters the development of the metabolic syndrome [54] and IR [55]. Because it controls the levels of calcium (Ca^{+ 2}) within cells, vitamin D has a more significant regulatory influence on the production of insulin. Additionally, vitamin D ultimately influences parathyroid hormone levels in the pancreas, which in turn regulates insulin production and secretion, as in Fig. 5. Through controlling insulin receptor expression, vitamin D controls insulin sensitivity. Vitamin D reduction is another crucial stage in IR stimulation. Vitamin D modulation restores Ca^{+ 2}, and ROS levels reach normal levels during DM and increase in $\beta$ -cells. Low levels of 1,25(OH)₂D are related to chronic kidney injury, a complication of type 2 DM. In these people, low vitamin D levels increase the risk of end-stage renal disease, all-cause mortality, and CVD [56, 57].

5. Conclusion

According to this study, nutritional deficits in vitamin D may encourage the development of COVID-19 and aggravate the condition. Thus, vitamin D may strengthen the immune system, stop the virus from spreading, and stop the disease from getting worse to a dangerous point. If a patient needs food therapy, it should be a part of their treatment plan to survive this potentially fatal condition and recover faster and better. Appropriate dietary supplementation and malnutrition screening are necessary for COVID-19 patients.

Author contributions

Conception: Hiba Sh. Ahmed, Hind Sh. Ahmed, Haylim N. Abud.

Methodology: Hiba Sh. Ahmed, Hind Sh. Ahmed.

Data collection: Hiba Sh. Ahmed, Haylim N. Abud.

Interpretation or analysis of data: Hiba Sh. Ahmed, Hind Sh. Ahmed, Haylim N. Abud.

Preparation of the manuscript: Hiba Sh. Ahmed, Hind Sh. Ahmed, Haylim N. Abud.

Revision for important intellectual content: Hiba Sh. Ahmed, Hind Sh. Ahmed, Haylim N. Abud.

Funding

This article has no funding support.

Ethical approval

The Institutional Scientific Committee has approved this study according to the Declaration of Helsinki for human studies.

Footnotes

Acknowledgments

The authors thank the Department of Chemistry/ College of Education for Pure Science (Ibn Al-Haitham)/ University of Baghdad and the Department of Microbiology/College of Science/ Al-Karkh University for Science for their approval of this work.

Conflict of interest

All Authors have no conflict of interest.

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The role of vitamin D against COVID-19 infection,progression and severity

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2.1 Diagnosis of coronavirus disease

2.2 Mitochondrial dynamics and viral infection

3. Results

3.3 Studies informed by vitamin D levels measured during COVID-19

Table 1 Comorbidity prevalence among all patients, including those on ventilators or ICU

5. Conclusion

Author contributions

Funding

Ethical approval

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Comorbidity prevalence among all patients, including those on ventilators or ICU