Vitamin D vs COVID: Part 4 of a series

Is it even possible to die of COVID with adequate vitamin D levels? Let's look at population studies.

COVID is widely considered to be a serious disease, with a generally agreed infection fatality rate (IFR) of 0.15% by February 2021  [1] which is similar to annual influenza IFR.  This was measured during a year in which treatments that had been well-studied against COVID were rarely used in western hospitals.  Because there are a number of well-researched, and widely used therapeutics against COVID, and many of these have been used in the home setting, rather than reported as “cases,” it is likely that the true IFR is lower than 0.15%.

Early on in the COVID era, it became clear that the time-honored and well-understood immune-regulatory and anti-viral effect of Vitamin D was clearly applicable as a preventive agent, and many independent clinicians around the world recommended it to our patients, with early support in the medical literature. [2] 

The first three articles in this series discussed the various functions of the human immune system and vitamin D’s influence on those functions, and particularly related to viral infections. 

However, not all of vitamin D’s actions against SARS-CoV-2 has directly involved what is commonly considered the immune system.  SARS-CoV-2 enters cells on the ACE-2 receptor.  ACE-2 is essential in the renin-angiotensin-aldosterone system (RAAS), typically considered primarily involved in homeostasis of sodium, water and blood pressure.  But RAAS is also present in the cells of the lungs’ alveoli, and is closely correlated with lung injury. [3]  ACE was found to be significantly elevated in COVID diagnosed patients. [4]  Vitamin D thwarts this SARS-CoV-2 invasive mechanism by inhibiting renin production in the kidneys.  [5]

COVID shows a similar demographic profile of mortality as the vitamin D-deficient cohorts, affecting those of advanced age, darker skin color, and higher BMI than other populations, in this study of 17,278,392 patients, examining over 10,000 deaths. [6]  A CDC study found 78% of people who were hospitalized for COVID were overweight or obese. [7]  Geographic distribution away from the equator was positively correlated with COVID mortality rates.  In fact, all countries within 35 degrees latitude away from the equator have had low mortality from COVID. [8]   In twenty European countries, a significant inverse relationship was found between serum vitamin D levels and COVID mortality.  Aging populations, which have had the most severe COVID experiences, were found to have the lowest mean serum levels of vitamin D. [9]

People with positive PCR results for COVID had statistically significant low vitamin D serum levels compared to those with negative PCR test results. [10]  [11] [12] [13] However, this may have been due to an expected drop in measurable vitamin D after infection.  But in a study of 14,000 patients in Israel, who had previously measured vitamin D levels, it was found that even prior, rather than current, high levels of vitamin D were associated with almost no COVID hospitalization, especially in the over 60 age group. [14]  It was remarkable that vitamin D levels over 75 nmol/l were associated with exceptionally little COVID in seniors.  Regardless of age, gender and co-morbidities, in a university hospital study in Germany of 185 patients, who were diagnosed with and treated for COVID, there was 80% less risk of ventilator need and 90% lower mortality among those with adequate vitamin D levels. [15]  In a much larger study of over 190,000 people in the US, vitamin D levels measured in the serum were strongly inversely related to SARS-CoV-2 positive PCR test results, regardless of age, race, gender and geographic area of residence.  Here is their graph of results: [16]

 

H Kaufman, J Niles. https://pubmed.ncbi.nlm.nih.gov/32941512/

A study of people testing positive for COVID in India found that those with higher vitamin D levels were significantly more likely to be asymptomatic than those with lower levels.  In that study, of hospitalized COVID patients, those with normal vitamin D levels had 15% of the mortality rate of those with low vitamin D levels. [17]

Mortality of hospitalized COVID patients has been found to be significantly higher among those with lower serum vitamin D levels. [18] [19] [20]  Conversely, vitamin D was positively correlated with survival of hospitalized COVID patients, in alignment with prior and worldwide results.  Another study of 551 COVID patients showed strong correlation between low vitamin D levels and mortality, even more strongly associated than BMI and mortality. [21]  Over 1500 patients across five UK hospitals showed similar and strong risk reduction for COVID mortality with supplemented vitamin D3. [22]  A similar US study also showed decreased mortality with higher serum levels of vitamin D. [23]  An analysis of 19 European countries from March 2020 through January 2021 showed that lower mean 25-hydroxy vitamin D serum levels correlated with higher COVID mortality. [24]  Another study of 18 European countries found similar COVID results, with a significant inverse correlation between latitude and vitamin D levels, and also with survival from COVID. [25]

An especially critical phase of pathogenesis in severe COVID disease has been the life-threatening cytokine storm.  It is an inflammatory over-reaction to the replicating viral pathogen, likely more pronounced due to its late onset, discussed above.  Vitamin D may have a crucial role in prevention of excessive inflammatory cytokines.  [26] [27] [28] [29]

Acute respiratory distress syndrome is the most iconic characteristic of SARS (Severe Acute Respiratory Syndrome).   Vitamin D deficiency was found to be common in people who develop ARDS. [30]  [31] Severe acute hypoxemia was correlated with low vitamin D levels in this retrospective study of 348 hospitalized patients in Italy. [32]

At this writing, a real-time meta analysis of 191 studies shows statistically significant improvements in mortality, ICU admissions and hospitalization.   Of these, vitamin D sufficiency studies show a strong association with outcomes.  33 of these studies over 14 different countries used vitamin D alone and show statistically significant improvement.   [33]

This graph shows a strong correlation between vitamin D status and COVID mortality.  [34]   [35]

Is it possible that COVID is another name, perhaps an additional name, for a deficiency of vitamin D? 

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[1] J Ioannidis.  Reconciling estimates of global spread and infection fatality rates of COVID-19: An overview of systematic evaluations.  Mar 26 2021.  Eur J Clin Inves.  https://onlinelibrary.wiley.com/doi/10.1111/eci.13554

[2] W Grant, H Lahore, et al.  Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.  Nutr Mar 12 2020.  12 (4).  988.  https://www.mdpi.com/2072-6643/12/4/988.

[3] L Chen, X Yang, et al.  Dysregulated renin-angiotensis system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice.  Nov 2013.  40 (5).  420-429.  https://journals.lww.com/shockjournal/Fulltext/2013/11000/Dysregulated_Renin_AngioteNsin_System_Contributes.12.aspx

[4] R Mardani, A Alamdary, et al.  Association of vitamin D with the modulation of the disease severity in COVID-19.  Virus Res.  Nov 2020.  289 (198148).  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455115/

[5] M Peng, W Liu, et al.  Immunological aspects of SARS-CoV-2 infection and the putative beneficial role of vitamin D.  May 16 2021.  Int J Mol Sci.  https://pubmed.ncbi.nlm.nih.gov/34065735/

[6] E Williamson, A Walker, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature.  Aug 2020.  584 (7821).  430-436.  https://pubmed.ncbi.nlm.nih.gov/32640463/

[7] CDC. Body mass index and risk for COVID-19-related hospitalization, intensive care unit admission, invasive mechanical ventilation, and death – United States, March-December 2020.  Mar 12 2021.  MMWR. 70 (10).  355-361.  https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e4.htm?s_cid=mm7010e4_w

[8] J Rhodes, S Subramanian, et al.  Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North support vitamin D as a factor determining severity.  Aliment Pharmacol Ther.  Jun 2020.  51 (12).  1434-1437.  https://pubmed.ncbi.nlm.nih.gov/32311755/

[9] P Ilie, S Stefanescu, et al.  The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.  Aging Clin Exp Res.  Mar 30 2020.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202265/pdf/40520_2020_Article_1570.pdf

[10] A D’Avolio, V Avataneo, et al.  25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.  Nutrients. Apr 20 2020. 12 (5).  https://www.mdpi.com/2072-6643/12/5/1359

[11] M Demir, F Demir, et al.  Vitamin D deficiency is associated with COVID-19 positivity and severity of the disease. J Med Vir.  Jan 29 2021.  https://onlinelibrary.wiley.com/doi/10.1002/jmv.26832

[12] A Abdollahi, H Sarvestani, et al.  The association between the level of serum 25(OH) vitamin D, obesity and underlying diseases with the risk of developing COVID-19 infection: A case-control study of hospitalized patients in Tehran, Iran.  J Med Virol.  Dec 12 2020.  https://onlinelibrary.wiley.com/doi/10.1002/jmv.26726

[13] A Faniyi, S Lugg, et al.  Vitamin D status and seroconversion for COVID-19 in UK healthcare workers.  Eur. Respir J 2020.  https://erj.ersjournals.com/content/erj/early/2020/11/26/13993003.04234-2020.full.pdf

[14] E Merzon, D Tworowski, 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 Sep 2020.  287 (17): 3693-3702.  https://pubmed.ncbi.nlm.nih.gov/32700398/

[15] A Radukovic, A Hippchen, et al.  Vitamin D deficiency and outcome of COVID-19 patients.  Nutrients Sep 1 2020.  12 (9).  2757.  https://www.mdpi.com/2072-6643/12/9/2757/htm

[16] H Kaufman, J Niles.  SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels.  PLoS One.  Sep 17 2020.  15 (9). E00239252.  https://pubmed.ncbi.nlm.nih.gov/32941512/

[17] A Jain, R Chaurasia, et al.  Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers.  Sci Rep.  Nov 19 2020.  10 (1) 20191.  https://pubmed.ncbi.nlm.nih.gov/33214648/

[18] A Radujkovic, T Hippchen.  Vitamin D deficiency and outcome of COVID-19 patients.  Nutrients. Aug 9 2020.  12 (9). 2757.  https://www.mdpi.com/2072-6643/12/9/2757/htm

[19] H Susianti, C Wahono, et al.  Low levels of vitamin D were associated with coagulopathy among hospitalized coronavirus (COVID-19) patients: a single-centered study in Indonesia.  J Med Biochem  Feb 12 2021.  https://aseestant.ceon.rs/index.php/jomb/article/view/30228

[20] M Infante, A Buoso, et al.  Low vitamin D status at admission as a risk factor for poor survival in hospitalized patients with COVID-19: An Italian retrospective study.  J Am Coll Nutrition.  Oct 31 2020.  https://www.tandfonline.com/doi/full/10.1080/07315724.2021.1877580

[21] P Vanegas-Cedillo, O Bello-Chavolla, et al.  Serum vitamin D levels are associated with increased COVID severity and mortality independent of visceral adiposity.  MedRxiv.  Mar 14 2020.  https://www.medrxiv.org/content/10.1101/2021.03.12.21253490v2

[22] S Ling, E Broad, 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.  Nov 15 2020.  12 (12). 3799.  https://www.mdpi.com/2072-6643/12/12/3799/htm

[23] N Charroenngam, A Shirvani, et al.  Association of vitamin D status with hospital morbidity and mortality in adult hospitalized COVID-19 patients.  Endo Practice.  Mar 8 2021.  https://www.endocrinepractice.org/article/S1530-891X(21)00057-4/fulltext

[24] A Ahmad, C Heumann, et al.  Mean vitamin D levels in 19 European countries & COVID-19 mortality over 10 months.  MedRxiv.  Mar 12 2021.  https://www.medrxiv.org/content/10.1101/2021.03.11.21253361v1

[25] S Walrand.  Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor.  Sci Rep.  Jan 21 2021. 11 (1981). https://www.nature.com/articles/s41598-021-81419-w

[26] J Cannell, R Vieth, et al.  Epidemic influenza and vitamin D.  Epidem Inf.  Sep 7 2006.  134 (6).  1129-1140. https://www.cambridge.org/core/journals/epidemiology-and-infection/article/epidemic-influenza-and-vitamin-d/C4D90C6E7CB127E6DF7A52D3A9EE2974

[27] L Pedersen, F Nashold, et al.  1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking.  J Neurosci Res.  85 (11).  2480-2490.  https://europepmc.org/article/MED/17600374

[28] N Giarratana, G Penna, et al.  A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development.  J Immunol.  Jul 31 2004.  173 (4).  2280-2287.  https://europepmc.org/article/MED/15294940

[29] C Gysemans, A Cardozo, et al.  1,25-dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice.  Endocrin.  Jan 5 2005.  146 (4).  1956-1964.  https://europepmc.org/article/MED/15637289

[30] R Dancer, D Parekh, et al.  Vitamin D deficiency contributes directly to the acute respiratory distress syndrome.  Thorax. Jul 2015.  70 (7).  617-624.  https://pubmed.ncbi.nlm.nih.gov/25903964/

[31] A Sulli, E Gotelli, et al.  Vitamin D and lung outcomes in elderly COVID-19 patients.  Nutrients.  13 (3)  Jan 2021.  https://www.mdpi.com/2072-6643/13/3/717

[32] G Mazziotti, E Lavezzi, et al.  Vitamin D deficiency, secondary hyperparathyroidism and respiratory insufficiency in hospitalized patients with COVID-19.  J Endo Inves.  Mar 5 2021.  https://link.springer.com/article/10.1007/s40618-021-01535-2

[33] Covid Analysis Vitamin D for COVID-19: real-time meta analysis of 191 studies. Apr 2 2022.  https://c19vitamind.com/

[34] P Raharusuna, et al.  Patterns of COVID-19 mortality and vitamin D: An Indonesian study.  Apr 26 2020.   https://drive.google.com/file/d/1dJ1VNakIvXBUEvqoQeV8FL8-R1PSgMJz/view

[35] L Borsche, et al.  Covid-19: More deaths? More lockdown?  More suffering? Graph by Dr. B Glauner.   https://borsche.de/res/Vitamin_D_Essentials_EN.pdf