Overcoming micronutrient deficiencies such as zinc and vitamins C, D, and K2 has attracted attention as a potential part of building a strategic response to the COVID-19 pandemic. Research that supports vitamin D supplementation is already convincing and is rapidly gaining in importance by government and the public. Vitamin K stays in the shadows for a long time, but recent research suggests it could benefit the immune system.
Vitamin D for immunity
Several meta-analyzes have already shown the benefit of vitamin D against respiratory tract infections; low vitamin D levels are associated with a higher risk of infection and severity of symptoms.1-4 Similar findings have been published regarding the association between low levels of vitamin D and a higher risk of SARS-CoV-2 infection.5-12
D, K2: Common connection with calcium
Vitamin D intake is usually considered safe, but high doses of vitamin D can cause short-term hypercalcemia, a temporary increase in serum calcium levels.13 Calcium, although crucial for the normal function of the human body, can have harmful consequences when it cannot be properly absorbed into the bone matrix.14 Calcium deposition in blood vessels or on elastic fibers in the lungs can lead to damage.15,16,17 Vitamin K2 supplementation may reduce this risk of calcification.14
Thanks to the common connection with calcium metabolism, vitamins D and K can act in pairs on the health of bones, blood vessels and the immune system. But scientists assume that the intake of vitamin D in a state of vitamin K deficiency could endanger both lung and vascular health.13,18,19 This could be even more important in patients with COVID-19, whose lungs and vascular health are already at risk. Therefore, taking the right amount of vitamin K2 in the circulation together with D can be a better strategy. Furthermore, research indicates the potential involvement of vitamin K in COVID-19 coagulopathy, which goes beyond alleviating the risk of calcification caused by high vitamin D intake.13
Vitamin K2: Underestimated vitamin
Vitamin K2 deficiency is thought to be common in Western populations for dietary reasons.14 Due to their structural differences, vitamins K1 and K2 have different metabolic outcomes.20.21 K1 is taken directly by the liver, where it is used to activate vital coagulation factors. K2, on the other hand, is available to the rest of the body to activate different but equally crucial proteins. They incorporate calcium into the bone matrix in the bone. In soft tissues such as blood vessels or lungs, they prevent the deposition of calcium, the breakdown of elastic fibers, thrombosis and inflammation.13
Implications of K2 in COVID-19
Recent research shows that poor outcomes of COVID-19 correlate with low vitamin K status.22 A recent study evaluating serum vitamin K levels in hospitalized patients with COVID-19 found that those with poor COVID-19 outcome had the lowest levels of vitamin K. In comparison, people who tested negative for SARS-CoV- 2 showed adequate vitamin K levels. Surprisingly, an unpublished study showed that patients with sufficient D levels accelerated the breakdown of elastic fibers, compared with those with mild deficiency. The study authors explained that by promoting the production of K-dependent proteins, vitamin D may have adverse procalcification effects and that vitamin K may compensate for the latter.
Another unpublished study later confirmed this association; K2 status was significantly lower among COVID-19 patients, and statistical analysis showed that mortality among COVID-19 patients strongly depended on vitamin K status. “This suggests that vitamin K plays a role in disease mechanisms,” the authors noted.
‘The Missing Link’ in COVID-19
The British Journal of Nutrition has published a review of the available scientific literature on vitamin K metabolism and its association with COVID-19.13 The authors presented vitamin K deficiency as a potential link missing between lung damage and thromboembolism, two of the most severe outcomes reported with COVID-19.
Vitamin K2 has also been described as one of the best potential ligands of the recently discovered fatty acid binding site in the SARS-CoV-2 helical protein.23 Studies suggest that its binding would stabilize the locked conformation of the spikes, thus reducing the possibility of interaction with ACE2 receptors (through which SARS-CoV-2 enters host cells), limiting the risk of infection.
K2 for the immune system
Vitamin K can also play a role in the body’s response to inflammation.24 Scientific support indicates the role of vitamin K in the modulation of the cellular signaling complex, the nuclear factor kappa-B (NF-kB).25 This major transcription factor helps regulate the genes responsible for both innate and adaptive immune responses. Vitamin K can regulate the activation of the NF-κB pathway, modulating the immune and inflammatory response. Similarly, vitamin K inhibits the release of cytokines, among which the potent cytokine interleukin (IL) -6,26 used as an inflammatory marker for severe COVID-19 infection with a poor prognosis, recorded several exhibitors at a virtual cardiovascular conference held in April 2020 by Imperial College London.
Research is ongoing
A clinical trial investigating the possible benefits of vitamin K2 supplementation in patients with COVID-19 was initiated by Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. Funded by Kappa Bioscience, a randomized, double-blind, placebo-controlled trial of “KOVIT” aims to assess whether vitamin K status affects the degradation of elastic fibers in the lungs. The research will be led by two doctors – pulmonologist dr. Rob Janssen and investigator coordinator Jona Walk, MD, specializing in internal medicine.
“Additional experimental evidence is needed to link vitamin K deficiency to COVID-19 pathology and to determine whether vitamin K2 supplements have a place in treatment protocols,” Janssen explained in detail. “The potential role of vitamin K2 supplementation in preventing the development of severe COVID-19 in individuals who are not yet infected with COVID-19 but are at risk of infection is also very important to assess.”
Kappa Bioscience AS enters into research contracts with several research centers in Europe and the USA. The company aims to support research to create a better understanding around vitamin K2 deficiency and the pathogenesis of COVID-19.
Based on recently published science, it is important to seek more understanding of the potential role of vitamin K2 in COVID-19 and immune health through research collaboration with experts in the field.
Trygve Bergeland is vice president of science at Kappa Bioscience.
To read related content, click the following link to access “Immunity health is growing”Digital Journal.
1 Bergman P et al. “Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.” PloS One. 2013; 8 (6): e65835.
2 Martineau AR et al. “Vitamin D supplementation for the prevention of acute respiratory tract infections: a systematic review and meta-analysis of data on individual participants.” BMJ. 2017; 356: i6583.
3 Pham H et al. “Acute respiratory tract infection and 25-hydroxyvitamin D concentration: a systematic review and meta-analysis.” Int J Environ Res Public Health. 2019; 16 (17): 3020.
4 Zhou YF, Luo BA, Qin LL. “The association between vitamin D deficiency and community-acquired pneumonia: a meta-analysis of observational studies.” The cure. 2019; 98 (38).
5 Ali N. “The role of vitamin D in the prevention of infection, progression and severity of COVID-19”. J Infectious public health. 2020; 13 (10): 1373-1380.
6 D’Avolio A et al. “25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.” Nutrients. 2020; 12 (5): 1359.
7 Ilie PC, Stefanescu S, Smith L. “The role of vitamin D in the prevention of infection and mortality from coronavirus disease 2019.” Aging Clin Exp Res. 2020: 1-4.
8 Im JH et al. “Nutritional status of patients with COVID-19.” Int J Infect Dis. 2020; 100: 390-393.
9 Kaufman HW et al. “SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels.” PLoS One. 2020; 15 (9): e0239252.
10 Meltzer DO et al. “Association of vitamin D status and other clinical features with COVID-19 test results.” JAMA Netw Open. 2020; 3 (9): e2019722-e2019722.
11 Panagiotou G et al. „Low serum 25-hydroxyvitamin D (25 [OH] D) levels in patients hospitalized with COVID-19 are associated with higher disease severity. “Clin Endocrinol. 2020; 93 (4): 508-511.
12 Radujković A et al. “Vitamin D deficiency and patient outcome with COVID-19.” Nutrients. 2020; 12 (9): 2757.
13 Janssen R et al. “Vitamin K metabolism as a potential link missing between lung damage and thromboembolism in Covid-19.” Br J Nutr. 2020; 1-25.
14 Maresz K. “Proper use of calcium: vitamin K2 as a promoter of bone and cardiovascular health.” Integr Med: Clin J. 2015; 14 (1): 34.
15 Lutsey PL, Michos ED. “Risk of Vitamin D, Calcium, and Atherosclerosis: Evidence from Serum Levels and Supplementation Studies.” Curr Atheroscler Rep. 2013; 15 (1): 293.
16 Sung KC et al. “High levels of serum vitamin D are associated with a reduced risk of metabolic diseases in men and women, but an increased risk of coronary artery calcification in Korean men.” Cardiovasc Diabetol. 2016; 15 (1): 112.
17 Wang J et al. “Vitamin D in vascular calcification: a double-edged sword?” Nutrients. 2018; 10 (5): 652.
18 Price PA, Buckley JR, Williamson MK. “Amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits arterial, cartilage, lung, and kidney calcification in vitamin D-induced rats.” J Nutr. 2001; 131 (11): 2910-2915.
19 Van Ballegooijen AJ et al. “Joint association of vitamins D and K with long-term outcomes in stable kidney transplant recipients.” Nephrol dial transplantation. 2020; 35 (4): 706-714.
20 Vermeer CV. “Vitamin K: Health Effect Outside Coagulation – A Review.” Food Nutr Res. 2012; 56 (1): 5329.
21 Schurgers LJ, Vermeer CV. “Differential pathways of vitamin K lipoprotein transport in healthy subjects.” Biochim Biophys Acta Gen Subj. 2002; 1570 (1): 27-32.
22 Dofferhoff ASM et al. “Decreased status of vitamin K as a potentially modified risk factor for severe coronavirus disease 2019.” Clin Infect Dis. 2020: ciaa1258.
23 Shoemark DK et al. “Molecular simulations suggest that vitamins, retinoids and steroids are ligands of the free pocket fatty acids SARS-CoV-2 protein spikes.” Angewandte Chemie. 2021; 60 (13): 7098-7110.
24 Reddy K et al. “The production of interleukin 6 by human lipopolysaccharide-stimulated fibroblasts strongly inhibits naphthoquinone (vitamin K) compounds.” Cytokine. 1995; 7 (3): 287-290.
25 Ghosh S, Dass JFP. “Study of cross-pathway interactions with NF-κB leading to its activation by ubiquitination or phosphorylation: A brief overview.” Gene. 2016; 584 (1): 97-109.
26 Rossol M et al. “LPS-induced cytokine production in human monocytes and macrophages.” Crit Rev Immunol. 2011; 31 (5): 379-446.