• Users Online: 165
  • Print this page
  • Email this page

 
Table of Contents
EDITORIAL
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 135-137

Vitamin D and COVID prevention: Hype? or hope?


Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Sakra World Hospitals, Bengaluru, Karnataka; Department of Medicine and Endocrinology, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences University, Chennai, Tamil Nadu, India

Date of Submission06-Aug-2020
Date of Acceptance06-Aug-2020
Date of Web Publication27-Oct-2020

Correspondence Address:
C V Harinarayan
Department of Medicine and Endocrinology, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences University, Chennai, Tamil Nadu
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCSR.JCSR_66_20

Rights and Permissions

How to cite this article:
Harinarayan C V. Vitamin D and COVID prevention: Hype? or hope?. J Clin Sci Res 2020;9:135-7

How to cite this URL:
Harinarayan C V. Vitamin D and COVID prevention: Hype? or hope?. J Clin Sci Res [serial online] 2020 [cited 2020 Nov 25];9:135-7. Available from: https://www.jcsr.co.in/text.asp?2020/9/3/135/298958



COVID-19 is caused by SARS-Co V-2 virus. The disease outbreak is a global pandemic impacting our communities. The virus binds to angiotensin-converting enzyme 2 (ACE2) receptors of Type II pneumocytes leading to decrease in the surfactant levels and increased surface tension in COVID-19. Protective immune response in the early stage of the disease is responsible for eliminating the virus. With the disease progression, there is a release of pro-inflammatory cytokines, interleukins (IL)-1B and IL-18 by activated macrophages and type 1 T helper (Th1) immune cells leading to lung inflammation and fibrosis. There is substantial higher risk among older patients and immunocompromised. The phases of immune response occurs: Asymptomatic mild infection, hyper-inflammatory response and immune paralysis.[1]

Vitamin D is a secosteroid and plays a major role in calcium homeostasis. The extraskeletal benefits are genomic (mediated by nuclear Vitamin D receptor [VDR]) and non-genomic effect on gene expression which involves the activation of signalling molecules. Vitamin D plays an essential role in the regulation of immunity in viral infections. Various immune cells, such as T-cells and B-cells, monocytes, macrophages and dendritic cells are capable of converting 25(OH)D to 1,25(OH)2D3. Binding of 1,25(OH)2D3 to VDR modifies gene expression and induces the production of peptides Cathelicidin and Defensins which have anti-microbial effects against fungi, bacteria and enveloped viruses (coronavirus). The production of Th1, cytokines interferon and tumor necrosis factor-α (TNF-α) are decreased by Vitamin D. Furthermore, there is an increase in the expression of anti-inflammatory cytokines and reduced the expression of pro-inflammatory cytokines by Vitamin D. 1,25(OH)2D3 interferes with macrophages, B- and T-lymphocytes, neutrophils and dendritic cells of the immune system which expresses VDR.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to ACE2 dysfunction. This leads to increase pro-inflammatory reactions and blood pressure [Figure 1]. Angiotensin II activates AT1R leading to a series of pro-inflammatory stimuli in the immune system and favour the development of inflammation, hypertension and diabetes. Nuclear factor kappa beta (NF-κB) is activated by Angiotensin II. Vitamin D is considered to counter and normalise this reaction of immune function. Most of these process initiated by Vitamin D occurs together with Vitamin A.[2] The dysregulation of the renin-angiotensin system leads to cytokine activation resulting in potentially fatal acute respiratory distress syndrome. The risk of COVID-19 infection and mortality is reduced by Vitamin D. The possible mechanisms are inhibiting Type 1 T-helper cell response, and stimulating T-cell induction, maintaining cell junctions and gap junctions, increasing cellular immunity by decreasing cytokine storm with influence of TNF-α and interferon-γ.[3],[4] It is also observed that Vitamin D sufficiency is known to reduce unfavourable downstream immunological squeal such as interleukin 6 elevation, delayed interferon-γ response which are negative prognostic marker in acutely ill coronavirus disease (COVID-19) pneumonia.[5],[6]
Figure 1: Vitamin D-RAS-COVID-19. In the classical pathway, renin cleaves angiotensinogen to Ang I which is converted to Ang II by ACE. Ang II acts through AT1R to produce effects as increase in catecholamine, vasoconstriction, blood pressure, inflammation and cardiac hypertrophy. Ang II suppresses renin through AT1R. The counter regulatory pathway is activated with the cleavage of Ang I to Ang 1–9 through ACE2 or AT2R activation or Ang II to Ang 1–7 which counter regulates through Mas receptor. Increase in aldosterone will block activities of ACE2 and attenuates the counter regulatory pathway (shaded square box). 1,25(OH)2D3lowers renin synthesis through the negative expression of renin gene independent of Ang II. SARS-CoV2 infection disrupts the counter regulatory pathway via ACE2 dysfunction. This leads to increase pro-inflammatory reactions and blood pressure. NF-κB is activated by Ang II through AT1R receptors (arrow not shown). Vitamin D can effectively inhibit NF-κB which is more efficient if VDR is unregulated. Ang II activates AT1R leading to a series of pro-inflammatory stimuli which are increased expression of MCP-1, Chemokine receptor CCR2 leading to massive infiltration of endothelium with macrophages. Similar event applies to activation, maturation and migration of DCs and antigen uptake/processing. The proinflammatory state is further promoted by the negative effect on T-lymphocytes and T-regulatory cells. This pro-inflammatory proves favor inflammation, hypertension and diabetes. Vitamin D counteracts these events leading to normalisation of immune function through a variety of ways. RAS = Renin-angiotensin system; VDR = Vitamin D receptor; Ang = Angiotensin; ACE = Angiotensin-converting enzyme; AT1R = Angiotensin receptor-1; DCs = Dendritic cells; NF-κB = Nuclear factor kappa beta; Ag = Antigen; Treg = Regulatory T-cells; AT2R = Angiotensin receptor-2; CoV2 = severe acute respiratory syndrome corona virus2; Mas = G protein coupled receptor for Ang 1-7; CCR2 = chemokine receptor 2; MPC-1 = mitochondrial pyruvate carrier 1

Click here to view


Vitamin D deficiency is an independent risk factor for diverse acute respiratory infections.[7] In a meta-analysis of 25 randomised control trials (RCTs) (participants n = 11,321), Vitamin D supplementation revealed modest protective effect on intervention (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.81–0.96).[8] There is a North-South gradient in COVID-19 outbreaks and particularly mortality.[9] The possible explanation being (a) older people of North European population with cardiopulmonary and metabolic co-morbidities and (b) high prevalence of Vitamin D deficiency in the Northern latitudes due to low ultraviolet exposure (now compounded by shut-downs). In winters, the virus survives longer outside the body because of low temperatures and relative humidity.[10] Furthermore, Vitamin D levels drop with age, which is an important factor as COVID-19-related case-fatality rate (CFR) surge with age. In a recent analysis, there was a strong negative correlation between the Vitamin D levels and COVID-19 cases (r = 0.444, P = 0.050).[11] An RCT has shown that the risk of developing respiratory tract infections is reduced by the prophylactic administration of Vitamin D (OR 0.64; 95% CI 0.49–0.84).[12] In Italy, Spain and France, the age-specific CFR of COVID-19 was the highest where there was severe Vitamin D deficiency in comparison to other countries.[13] There are retrospective observational studies pointing out the association between Vitamin D status and clinical outcomes. In a retrospective study of 212 patients with COVID-19 infection, Vitamin D levels correlated with the severity of disease. The mean Vitamin D level (nmol/L) was 78 (mild infection), 68.5 (ordinary) and 53 (severe and critical) (P < 0.001) COVID-19 infection, respectively.[14] In a recent population-based study (n = 7807) from Israel, low plasma 25(OH) D was an independent risk factor for COVID-19 infection and hospitalisation. In participants tested positive for COVID-19, Vitamin D levels were significantly low. Univariate analysis demonstrated increased likelihood for COVID-19 in participants with low Vitamin D (OR 1.58 65% CI 1.24–2.01 P < 0.001).[15] In the elderly population, there is a shortage of memory B-cells with over activation of adaptive immune system and aberrant innate immune response leading to cytokine storm in COVID-19 patients.[16] It is evident from the Vitamin D-RAS-COVID-19 interaction [Figure 1], the clinical outcomes will be poorer in patients with co-morbidities such as hypertension, diabetes, Vitamin D deficiency, immune compromised patients', pre-existing pulmonary pathologies and elderly.

Maintaining Vitamin D sufficiency does have a role in combating early infection. Having said there are many unanswered questions. It is documented that approximately 80% of Indian population have Vitamin D and dietary calcium deficiency in India.[17] India stands number three in COVID 19 infection (worldwide) (August 1, 2020) with 65% recovery rate and 2.15% CFR (fifth in the world). With Tuberculosis being rampant, the COVID-19 infection, recovery and mortality – is it different from other countries? Similar scenario for pulmonary sarcoidosis. With both the pulmonary diseases occurring in the background of Vitamin D deficiency is the clinical course of COVID-19 any different? COVID-19 alters the surfactant levels in the lungs. In a country like India with rampant Vitamin D deficiency, the neonates born of Vitamin D deficient mothers – do they have a higher risk? India being diabetes capital of the world, do we have a higher incidence of COVID-19 infections – is the clinical course and severity different from the other parts of the world? It appears the COVID positive elderly patients with co-morbidities and low Vitamin D levels are more at risk.

Lockdown had made the public stay indoors, further lowering the Vitamin D levels, more so in the elderly. There are no separate guidelines for Vitamin D supplementation in patients with COVID-19. Till, we have more RCTs to document the benefits of Vitamin D in COVID-19 it is prudent on our part to achieve Vitamin D sufficiency using the treatment guidelines pertinent to our country.[18]

As it stands we can presume that normal Vitamin D levels – protective immune response – no infection or asymptomatic and recovery. Vitamin D deficiency – more susceptible – more severe course of illness – more so if there are co-morbidities. Still, we have an unanswered question – do all persons with Vitamin D deficiency have unfavourable outcomes with COVID infection? While we click our tongues and raise our brows about the association of Vitamin D and COVID-19, Vitamin D is a hope, in that it is at least protective in the asymptomatic infection with no comorbidities. It is a hype to say that it will treat the severely ill COVID-19 patients after the cytokine storm has set in.



 
  References Top

1.
Praveen T, Desai D, Soneja M, Wig N. Immune dysregulation in COVID-19 and its therapeutic implications. J Clin Sci Res 2020;9:37-41.  Back to cited text no. 1
  [Full text]  
2.
Biesalski HK. Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship? NFS J 2020;20:10-21.  Back to cited text no. 2
    
3.
Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020;12:988.  Back to cited text no. 3
    
4.
Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. J Infect Public Health 2020. [doi: 10.1016/j.jiph. 2020.06.021].  Back to cited text no. 4
    
5.
Zdrenghea MT, Makrinioti H, Bagacean C, Bush A, Johnston SL, Stanciu LA. Vita-min D modulation of innate immune responses to respiratory viral infections. Rev Med Virol 2017;27:e1909.  Back to cited text no. 5
    
6.
Miroliaee AE, Salamzadeh J, Shokouhi S, Sahraei Z. The study of vitamin D administration effect on CRP and Interleukin-6 as prognostic biomarkers of ventilator associated pneumonia. J Crit Care 2018;44:300-5.  Back to cited text no. 6
    
7.
Joliffe DA, Griffiths, CJ, Martineau AR. Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. J Steroid Biochem Mol Biol 2013;136:321-9.  Back to cited text no. 7
    
8.
Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583.  Back to cited text no. 8
    
9.
Tian Y, Rong L, Nian W, He Y. Review article: Gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther 2020;51:843-51.  Back to cited text no. 9
    
10.
Panarese A, Shahini E. Letter: Covid-19, and vitamin D. Aliment Pharmacol Ther 2020;51:993-9.  Back to cited text no. 10
    
11.
Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res 2020;32:1195-8.  Back to cited text no. 11
    
12.
Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2013;8:1-4.  Back to cited text no. 12
    
13.
Daneshkhah A, Eshein A, Subramanian H, Roy HK, Backman V. The role of vitamin D in suppressing cytokine storm in COVID-19 patients and associated mortality. medRxiv 2020.  Back to cited text no. 13
    
14.
Alipio M. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with coronavirus-2019 (COVID-2019). 2020.  Back to cited text no. 14
    
15.
Merzon E, Tworowski D, Gorohovski A, Vinker S, Golan Cohen A, Green I, et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study. FEBS J 2020. [doi: 10.1111/febs. 15495].  Back to cited text no. 15
    
16.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020;71:762-8.  Back to cited text no. 16
    
17.
Harinarayan CV, Akhila H. Modern India and the tale of twin nutrient deficiency-calcium and vitamin D-nutrition trend data 50 years-retrospect, introspect, and prospect. Front Endocrinol (Lausanne) 2019;10:493.  Back to cited text no. 17
    
18.
Harinarayan CV. How to treat vitamin D deficiency in sun-drenched India – Guidelines. J Clin Sci Res 2018;7:131-40.  Back to cited text no. 18
  [Full text]  


    Figures

  [Figure 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
References
Article Figures

 Article Access Statistics
    Viewed1236    
    Printed4    
    Emailed0    
    PDF Downloaded89    
    Comments [Add]    

Recommend this journal