Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease
Scientific Reports volume 11, Article number: 10641 (2021)
Maheshwar Lakkireddy, Srikanth Goud Gadiga, R. D. Malathi, Madhu Latha Karra, I. S. S. V. Prasad Murthy Raju, Ragini, Sangeetha Chinapaka, K. S. S. Sai Baba & Manohar Kandakatla
- COVID-19 defeated 3x faster by 420,000 IU Vitamin D nanoemulsion – RCT Nov 12, 2020
- Inflammation reduced by a single dose of Vitamin D (200,000 IU) – RCT Jan 2016
- Inflammation is reduced by each of the following: Vitamin D, Omega-3, Diet
- Preprint version of this study in in VitaminDWiki:
- Guideline following hip fracture – 50000 IU vitamin D daily for 7 days – Jan 2013
- COVID-19 inflammation extinguished by 60,000 IU of vitamin D nanoemulsion daily for a week – RCT May 2021
- Hospitalized children with COVID-19 and inflammation had lower vitamin D – March 2021
- COVID-19 deaths are proportional to previous interleukin-6 levels, Vitamin D lowers them – Nov 2020
- Malaria in mice brains, and associated inflammation, prevented by Vitamin D intervention – July 2014
- As of June 18, the page had: 34 trials, 5 trial results, 17 meta-analyses and reviews, 59 observations, 34 recommendations, 53 associations, 88 speculations, 45 videos see related: Governments, HealthProblems, Hospitals, Dark Skins, 26 risk factors are ALL associated with low Vit D, Recent Virus pages Fight COVID-19 with 50K Vit D weekly Vaccine problems
Vitamin D nanosolution was used Deksel $0.83 per 60,000 IU bottle - one of many suppliers
Unclear if their nanosolution was a true nanoemulsion
Nanoemulsion vitamin D products have been found to have perhaps 2X more response and 4X faster
Many companies selling on Amazon make Vitamin D nanoemulsions
Nanoemulsion Vitamin D may be a substantially better form
87 total participants - mild to moderate symptoms, vitamin D level < 30 ng initially
The larger comparison groups VD ( treatment group) and NVD ( control group) received
Remdesivir, Favipiravir, Ivermectin or dexamethasone.
A subset of larger group ( eVD and eNVD) did not receive the above drugs and were measured for exclusive effect of vitamin D ( tables 4,5,6).
The slow increase in Vitamin D levels over a week allowed time for the virus to race ahead.
Suspect they would have had much better results if they had;
1) Give the entire 420,000 IU on the first day
2) Had the participants swish the vitamin D in their mouths
Vitamin D levels measured the day after the last dose generally > 80 ng (suspect that the plateau would be 20% higher)
Additional 2 days of vitamin D if BMI >25
The study used a website to estimate # of participants needed; openepi.com
Web-based epidemiological statistics to plan and analyze clinical trials
COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80–100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.
COVID-19 caused by SARS-CoV-2 (novel corona virus) has not only incited intense adaptive immune response in the individuals who were affected by it but also has incited immense human response at various fronts to fight it all over the world4,5. As the immune dysregulation caused by COVID-19 lead to respiratory failure and multi organ dysfunction syndrome, many attempts were made to repurpose the available drugs to address the challenges posed by the novel corona virus4,6,7,20,21. Mortality and morbidity were recorded to be high in patients with significantly elevated inflammatory markers (surrogate markers of COVID-19 severity) such as N/L ratio, CRP, LDH, IL6, Ferritin, D dimer etc3,6,7,11,22. Similarly, mortality and morbidity were also recorded to be high in patients with vit.D deficiency9,11,12. Low vit.D level was proposed to be an independent risk factor for acquiring COVID-19 infection, hospitalization and COVID-19 related mortality9,10. Based on the earlier evidence that vit.D could decrease the incidence of flu and other respiratory infections and the observational studies in COVID-19, few hypothesis and recommendations have been published in support of supplementing vit.D to avert the serious consequences of COVID-192,3,9,10,11,12,23,24. Kaufman et al. reported that SARS-CoV-2 positivity is strongly and inversely associated with serum vitamin D level and proposed that vitamin D supplementation could reduce the risk of SARS-CoV-2 infection and COVID-19 disease25.
Vit.D has innumerable effects on human physiology. In addition to its endocrinal and calcitropic musculoskeletal effects, it is a potential immunomodulator. Depending upon the prevailing internal milieu and the level of 25 hydroxy vitamin D in the blood, intracrinal activation of 1α hydroxylase occurs in the immune cells to produce calcitriol locally and have its autocrine effects like promotion of innate immune response to infections and modulation of adaptive immune response. Vit.D acts as a smart switch to decrease the Th1 response and pro inflammatory cytokines while enhancing the production of anti-inflammatory cytokines in cases of immune dysregulation13,14,15,16,23. It is pertinent to note that SARS-CoV-2 virus activates Th1 response and suppresses Th2 response4. It was postulated that the levels of vit.D above 40–60 ng/ml could be protective to tide over the COVID-19 crisis8,11,26. Annweiler et al. reported that the hospitalised frail elderly patients who had regularly taken bolus vitamin D supplementation before hospitalisation with COVID-19 had significantly better survival rates than others27. In a retrospective analysis, Ling et al. reported a reduced risk of mortality in COVID 19 patients treated with high dose cholecalciferol booster therapy28. Owing to the paucity of evidence from prospective randomised clinical trials, high dose vit.D was not included in the existing treatment protocols of COVID-19. Few randomised control trials using bolus doses of vitamin D in COVID-19 are yet to be completed and reported29. McNally et al. reported that rapid normalization of vitamin D levels can be achieved with loading therapy, duly considering the disease status, baseline vit.D level and weight but loading doses > 3,00,000 IU were advised to be avoided until trials are conducted to evaluate the risk and benefit30. Intermittent bolus dose vit.D therapies with 3 monthly gaps have failed to achieve the target levels31.
As the concentration dependent effects of vit.D on the immune system and the means to achieve such concentrations safely in the shortest possible time in a given individual is known19,30,32, we have carried out this study to determine the impact of Pulse D therapy on the inflammatory markers of COVID-19.
The two randomised groups in our study were matched with respect to age, BMI, duration of symptoms, co-morbidities and vital parameters. In spite of the matching of various parameters, significant difference in markers before treatment between the groups was intriguing. This difference can be attributed to chance alone. Male predominance (75% vs 25%) was noted akin to earlier reports3. Analysis of inflammatory markers before and after treatment in VD group has shown highly significant reduction (p < 0.01) in all the inflammatory markers after adjunctive pulse D therapy. On the contrary insignificant reduction (p > 0.05) of inflammatory markers was noted in the NVD group. The difference in reduction of inflammatory markers between the groups (NVD vs VD) was highly significant (p < 0.01) with the reduction of markers being markedly high in VD group when compared to the NVD group.
Hence, adjunctive Pulse D therapy targeted at a mean vit D level of 80-100 ng/ml has effectively reduced the inflammatory markers associated with cytokine storm and COVID-19 severity.
Rastogi et al. reported that high dose vit.D supplementation orally for seven consecutive days has increased the vit.D level in a group of 16 patients from 8.6 to 42.4 ng/ml with significant reduction in fibrinogen levels and insignificant reduction in CRP. Early viral clearance in the form of negative RT-PCR after vit.D supplementation was also reported1.
Entrenas Castillo et al. reported that oral administration of high dose calcifediol has significantly reduced the severity of COVID-19, need for ICU treatment and mortality. Though elevated levels of inflammatory markers at enrolment were reported, initial level of vitamin D or the follow up levels of vitamin D or inflammatory markers was not studied33.
It may be noted that the statistically significant reduction of all the inflammatory markers in this study may be attributed to the level of vit.D achieved (89 ± 32 ng/ml) and aqueol nano formulation (Deksel) has facilitated the target levels to be achieved, akin to an earlier report19. Significant reduction in CRP was noted in our study when compared to the report of Rastogi et al.1. This may be attributed to the difference in the level of vit.D after treatment. As per our knowledge, these finding are the first of its kind to be reported.
We have analysed the inflammatory markers in a separate subset of cases (eVD and eNVD sub groups) derived from both the study groups who have not received any drugs like Remdesivir, Favipiravir or Ivermectin or Dexamethasone. Highly significant reduction (p < 0.01) in all the measured inflammatory markers with significant increase in vit.D was noted in the eVD sub group unlike the eNVD sub group (p > 0.05). The difference in reduction of inflammatory markers between the sub groups (eNVD vs eVD) was highly significant (p < 0.01) with the reduction of markers being markedly high in eVD subgroup when compared to the eNVD sub group. Hence, improvement in serum vit.D level to 80 ng/ml has shown to effectively reduce the levels of surrogate markers of COVID-19 severity/cytokine storm independently. These findings are exclusive to our study as on date and could not be compared with others.
DiNicolantonio et al. reported that both magnesium and vitamin D are important to the immune system independently. Together, they may be beneficial in COVID-19 infection as magnesium is necessary to activate vitamin D. Results from our study can be compared with the results of future studies with and without magnesium in high dose vitamin D regimens to formulate effective dosing schedules34.
Hospital stay was subjective and multifactorial in both the groups. It could not be attributed to the physical impact of the disease alone. Murai et al. reported that, a single high dose vitamin D3 (2,00,000 IU) supplementation has not reduced the length of hospital stay, mortality or ICU admission significantly when compared to placebo. Their findings did not support the use of single bolus dose of vitamin D3 for treatment of moderate to severe COVID-1935.
At enrolment, significantly higher levels of all the inflammatory markers were noted in the non survivors compared to survivors. Similar relationship of mortality to the elevated levels of inflammatory markers was reported by Jain et al. in their observational study3.
No adverse reactions to vit.D were reported in our study. Serum calcium levels were within the normal limits after treatment (9 ± 0.5.mg/dl) in VD group. Similar finding on the safety of short-term high dose vit.D supplementation were reported by Rastogi et al. and in long term by McCullough et al.1,36. De Carvalho et al. reported that mega doses (6,00,000 IU) of vitamin D administered through intramuscular route even in cases of nephrolithiasis are safe37.
Immune dysregulation in COVID-19 is marked by increased inflammatory biomarkers such as N/L ratio, CRP, LDH, IL6 and Ferritin. Vitamin D is a potential immunomodulator and its adjunctive role in the treatment of COVID-19 is established by this study. Improvement of serum vit.D level to 80–100 ng/ml has significantly reduced the inflammatory markers without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19.
- Rastogi, A. et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study). Postgrad. Med. J. https://doi.org/10.1136/postgradmedj-2020-139065 (2020).
- Aygun, H. Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn. Schmiedebergs Arch. Pharmacol. 393(7), 1157-1160. https://doi.org/10.1007/s00210-020-01911-4 (2020).
- Jain, A. et al. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci. Rep. 10(1), 20191. https://doi.org/10.1038/s41598-020-77093-z (2020).
- Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223), 497-506. https://doi.org/10.1016/S0140-6736(20)30183-5 (2020).
- Ye, Q., Wang, B. & Mao, J. The pathogenesis and treatment of the ‘Cytokine Storm55 in COVID-195. J. Infect. 80(6), 607-613. https:// doi.org/10.1016/j.jinf.2020.03.037 (2020).
- Chen, L. et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 43, E005. https://doi.org/10.3760/cmaj.issn.1001-0939.2020.0005 (2020).
- Chen, G. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Invest. 130(5), 2620-2629. https://doi.org/10.1172/JCI137244 (2020).
- Grant, W. B. et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 12(4), 988. https://doi.org/10.3390/nu12040988 (2020).
- De Smet, D., De Smet, K., Herroelen, P., Gryspeerdt, S. & Martens, G. A. Serum 25(OH)D level on hospital admission associated with COVID-19 stage and mortality. Am. J. Clin. Pathol. https://doi.org/10.1093/ajcp/aqaa252 (2020).
- Merzon, E. 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. 287(17), 3693-3702. https://doi.org/10.1111/febs.15495 (2020).
- Maghbooli, Z. et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One 15(9), e0239799. https://doi.org/10.1371/journal.pone.0239799 (2020).
- Carpagnano, G. E. et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J. Endocrinol. Invest. 9, 1-7. https://doi.org/10.1007/s40618-020-01370-x (2020).
- Chambers, E. S. & Hawrylowicz, C. M. The impact of vitamin D on regulatory T cells. Curr. Allergy Asthma Rep. 11(1), 29-36. https://doi.org/10.1007/s11882-010-0161-8 (2011).
- Adams, J. S. & Hewison, M. Unexpected actions of vitamin D: New perspectives on the regulation of innate and adaptive immunity. Nat. Clin. Pract. Endocrinol. Metab. 4(2), 80-90. https://doi.org/10.1038/ncpendmet0716 (2008).
- Lemire, J. M. et al. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J. Immunol. 134(5), 3032-3035 (1985).
- Gombart, A. F., Pierre, A. & Maggini, S. A Review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients 12(1), 236. https://doi.org/10.3390/nu12010236 (2020).
- Meltzer, D. O. et al. Association of VITAMIN D status and other clinical characteristics with COVID-19 test results. JAMA Netw. Open. 3(9), e2019722. https://doi.org/10.1001/jamanetworkopen.2020.19722 (2020).
- Baeke, F., Takiishi, T., Korf, H., Gysemans, C. & Mathieu, C. Vitamin D: Modulator of the immune system. Curr. Opin. Pharmacol. 10(4), 482-496. https://doi.org/10.1016/jxoph.2010.04.001 (2010).
- Lakkireddy, M. et al. Efficiency of vitamin D supplementation in patients with mechanical low back ache. J. Clin. Orthop. Trauma 10(6), 1101-1110. https://doi.org/10.1016/jjcot.2019.06.018 (2019).
- Sanders, J. M., Monogue, M. L., Jodlowski, T. Z. & Cutrell, J. B. Pharmacologic treatments for coronavirus disease 2019 (COVID- 19): A review. JAMA 323(18), 1824-1836. https://doi.org/10.1001/jama.2020.6019 (2020).
- WHO Solidarity Trial Consortium et al. Repurposed antiviral drugs for covid-19-interim WHO Solidarity Trial Results. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2023184 (2020).
- Velavan, T. P. & Meyer, C. G. Mild versus severe COVID-19: Laboratory markers. Int. J. Infect. Dis. 95, 304-307 (2020).
- Liu, G., Hong, T. & Yang, J. A single large dose of vitamin D could be used as a means of coronavirus disease 2019 prevention and treatment. DrugDes. Dev. Ther. 21(14), 3429-3434. https://doi.org/10.2147/DDDT.S271754 (2020).
- Giannini, S. et al. Effectiveness of in-hospital cholecalciferol use on clinical outcomes in comorbid COVID-19 patients: A hypothesis-generating study. Nutrients 13(1), 219. https://doi.org/10.3390/nu13010219 (2021).
- Kaufman, H. W., Niles, J. K., Kroll, M. H., Bi, C. & Holick, M. F. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One 15(9), e0239252. https://doi.org/10.1371/journal.pone.0239252 (2020).
- Ebadi, M. & Montano-Loza, A. J. Perspective: Improving vitamin D status in the management of COVID-19. Eur. J. Clin. Nutr. 74(6), 856-859. https://doi.org/10.1038/s41430-020-0661-0 (2020).
- Annweiler, G. et al. Vitamin D supplementation associated to better survival in hospitalized frail elderly COVID-19 patients: The GERIA-COVID quasi-experimental study. Nutrients 12(11), 3377. https://doi.org/10.3390/nu12113377 (2020).
- Ling, S. F. et al. High-dose cholecalciferol booster therapy is associated with a reduced risk of mortality in patients with COVID- 19: A cross-sectional multi-centre observational study. Nutrients 12(12), 3799. https://doi.org/10.3390/nu12123799 (2020).
- Mariani, J. et al. High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial (CARED-TRIAL). Trials 22(1), 111. https://doi.org/10.1186/s13063-021-05073-3 (2021).
- McNally, J. D. et al. Rapid normalization of vitamin D levels: A meta-analysis. Pediatrics 135(1), e152-e166. https://doi.org/10.1542/peds.2014-1703 (2015).
- Valimaki, V. V., Loyttyniemi, E., Pekkarinen, T. & Valimaki, M. J. How well are the optimal serum 25OHD concentrations reached in high-dose intermittent vitamin D therapy? A placebo-controlled study on comparison between 100 000 IU and 200 000 IU of oral D3 every 3 months in elderly women. Clin. Endocrinol. (Oxf.) 84(6), 837-844. https://doi.org/10.1111/cen.13014 (2016).
- Wu, Z. et al. What factors modify the effect of monthly bolus dose vitamin D supplementation on 25-hydroxyvitamin D concentrations?. J. Steroid. Biochem. Mol. Biol. 201, 105687. https://doi.org/10.1016/j.jsbmb.2020.105687 (2020).
- Entrenas Castillo, M. et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J. Steroid. Biochem. Mol. Biol. 203, 105751. https://doi.org/10.1016/j.jsbmb.2020.105751 (2020).
- DiNicolantonio, J. J. & O'Keefe, J. H. Magnesium and vitamin D deficiency as a potential cause of immune dysfunction, cytokine storm and disseminated intravascular coagulation in COVID-19 patients. Mol. Med. 118(1), 68-73 (2021).
- Murai, I. H. et al. Effect of a single high dose of Vitamin D3 on hospital length of stay in patients with moderate to severe COVID- 19: A randomized clinical trial. JAMA 325(11), 1053-1060. https://doi.org/10.1001/jama.2020.26848 (2021).
- McCullough, P. J., Lehrer, D. S. & Amend, J. Daily oral dosing of vitamin D3 using 5000 to 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J. Steroid Bio. Mol. Biol. 189, 228-239. https://doi.org/10.1016/j.jsbmb.2018.12.010 (2019).
- de Carvalho, J. F. & Churilov, L. P. Safety of megadose of vitamin D in patients with nephrolithiasis. Nutrition 12(87-88), 111201. https://doi.org/10.1016/j.nut.2021.111201 (2021).