COVID: vitamin d deficiency may lead to worse outcomes

A recent article suggests a role for vitamin D in decreasing Covid-19 associated morbidity/mortality (see covid vitamin d dec crp in dropbox, or doi: https://doi.org/10.1101/2020.04.08.20058578). i do realize that this blog is a bit of a slog through some of the literature on vitamin D, but many of us may not appreciate the potential role of vitamin D in the immune system.

 

Details:

-- the researchers combined the following information:

    -- data from Covid-confirmed cases from Germany, South Korea, China, Switzerland, Iran, UK, US, France, Spain, Italy), as of April 20

    -- case mortality ratios were estimated as: the number of deceased patients on day N divided by the number of confirmed Covid cases on day N-8 (this is based on Wuhan studies suggesting that there was a median time lag of 8 days between hospital admission and time of death, and 14 days since the onset of symptoms; they chose N-8 since there was the least variation across countries, vs 14 days

    -- vitamin D: no actual data for Covid patients; they estimated the potential impact of vitamin D in reducing severe Covid-19 by comparing data between C-reactive protein (CRP) levels (which are decreased in those with adequate vitamin D), and between CRP and severe Covid-19 

--baseline 25(OH) vitamin D levels were assessed by prior epidemiologic studies in the elderly population (though not available for Italy and Spain)

 

Results:

--they confirmed that the overall risk of ICU care and mortality were increased in people >60yo

--the risk of severe Covid-19 among patients with likely vitamin D deficiency is 17.3% vs those with likely normal levels is 14.6%, a reduction of 15.6%

 

Commentary:

-- their focus in this study is especially for those >60 yo who have both higher incidence of cytokine storm and increased ICU admissions and mortality.

-- and, especially from data from China, that those with CRP levels >10mg/L were more likely to have severe Covid-19 infections (23% vs 8% in those with lower CRP levels); and those with severe Covid-19 infections were more likely to have high CRP levels (81% vs 19%)

-- it is notable that case fatality rates varied dramatically between countries: for example they are higher in Spain, Italy, and the UK compared to the US and Germany

-- their argument is as follows: the cytokine storm in Covid-19 is bad: inflammation (as measured by CRP levels) might instigate ARDS, exacerbate the effects of pneumonia, and lead to hypoxemia, acute kidney disease, acute heart failure, and rhabdomyolysis. And may be fatal. And low vitamin D levels may increase the differentiation of CD8+ cells into cytotoxic T lymphocytes by overactivation of the adaptive immune system and lead to increased cytokines after about 7 days. And these increased cytokine levels may lead to a higher likelihood of cytokine storm. Here are some of the studies supporting the role of vitamin D in immunologic responses:

    -- there are vitamin D receptors on several immunologic cells (including T and B lymphocytes, macrophages, dendritic cells), with some data suggesting that low vitamin D levels are associated with immune dysfunction

    -- also, there is a higher Covid-19 case fatality rate in the elderly, who typically have lower vitamin D levels at least in part because those over age 50 have less generation of vitamin D with the same amount of sunlight; also aging itself is associated with a weaker innate immune system response in the elderly, perhaps associated with a consequent overactivation of the adaptive immune system with high cytokine production (the innate immune system refers to the nonspecific response after an antigen presents itself: eg interferons, activation of complement cascade/activating cells/clearing antibody complexes, and activating the adaptive immune system; the latter being specialized cells that create immunological memory to a specific pathogen and enhanced subsequent response to encounters with that pathogen)

        -- so, vitamin D could potentially suppress cytokine production by boosting the innate immune system and decreasing this overactivation of the adaptive immune system

-- vitamin D has been shown to enhance immune response for flu and previous coronaviruses

-- for influenza, one purported mechanism is that influenza virus (both H1N1 and H5N1) induce a T helper 1 (Th1) response, associated with increased inflammatory cytokines (including IL-6 and TNFa)

        -- and vitamin D reduces the production of Th1 cells, shifting the balance of Th1/Th2 towards a less inflammatory Th2

        -- another study found that in vitamin D deficient elderly volunteers receiving vitamin D supplementation and then received influenza vaccine had lower TNFa and IL-6 levels as well as higher TFG-b levels (Transforming Growth Factor)

        -- there was an interesting report suggesting a relationship between higher ultraviolet B radiation (an indicator of the population vitamin D status) and lower case fatality rates from the 1918-19 influenza pandemic in the US

-- vitamin D up regulates human calthelicidin levels (an endogenous antibacterial peptide), with several studies suggesting this is effective against bacterial infections including mycobacteria tuberculosis. For example, an RCT found that people with active TB randomized to vitamin D repletion had improvement of several markers of TB-associated inflammatory responses (see vit d and tb treatment pnas 2012 in dropbox, or go to URL: www.pnas.org/cgi/doi/10.1073/pnas.1200072109​)​. One general  reference on vitamin D and the immune system is vit d dec inflam dermendo2009 in dropbox, or DOI:10.4161/derm.1.4.9063

-- there are studies suggesting that vitamin D receptor polymorphisms are associated with acute lower respiratory tract infection (especially bronchiolitis)

-- another study found a negative correlation between 25(OH) D levels and TNFa concentrations in serum of healthy women (see vit d dec TNFa jinflam2008 in dropbox, or doi: 10.1186/1476-9255-5-10

-- another argued that higher CRP levels are associated with coronary vascular disease (and, as per the JUPITER trial, lowering CRP levels in those with good LDL levels by rosuvastatin decreased these events dramatically), that low vitamin D levels were associated with CVD but only in those with high CRP levels (per the US NHANES study), so improving 25(OH)D levels by vitamin D supplements might be an important public health intervention: see vit d crp clincardiol2019 in dropbox, or DOI: 10.1002/clc.23189, and the NHANES study at  https://onlinelibrary.wiley.com/doi/full/10.1002/clc.23189

    --based on this HANES study, the researchers on the vitamin D link above found that the risk of a high CRP level, by vitamin D status:

        --normal vitamin D, 25-(OH)D >75 nmol/L: 45% had high CRP

        --insufficient vitamin D, 25-(OH)D 50-75 nmol/L: 50%

        --deficient vitamin D, 25-(OH)D 25-50 nmol/L: 45%

        --severely deficient vitamin D, 25-(OH)D <25 nmol/L: 63%

 

Limitations of the Chinese study above:

--the big one: assumption that vitamin D levels in Covid-19 patients reflects the pattern in the prior vitamin D studies in those countries (ie, there are no patient-level data showing that vitamin D levels track with Covid-19 outcomes)

--they did not incorporate age-specific Covid-19 mortality rates into their mortality data (some data from some countries were not available)

--there were very different SARS-CoV-2 testing strategies in different countries (though they did try to combine countries with similar approaches). So the collection of mortality data might have varied a lot between countries

so, a few points:

-- vitamin D receptors are on almost all cells in the body, suggesting evolutionarily that vitamin D has a role in many bodily functions and not just bone and muscle. (and, we did evolve from animals in the near equatorial regions, where they did not need vitamin D fortified milk to have enough vitamin D....)

-- in particular to Covid-19, vitamin D does have documented effects on the immune system, with deficiency associated with higher levels of inflammatory markers (and, another assumption: these increased inflammatory markers might be associated with development of cytokine storm and awful outcomes). and there is the anti-IL-6 monoclonal antibody (Tocilizumab) being trialed now

-- i have had many patients request vitamin C prescriptions as immune enhancers to prevent Covid-19 (since OTC vitamin C has been depleted in local pharmacies by popular demand). But this does give me the opportunity to:

    -- reinforce that there are not great studies of vitamin C's immunologic benefit

    -- that even if there were benefit, it is really important not to let down one's guard about social isolation, masks, hand washing

    -- and, that a much better choice is to take vitamin D supplements as appropriate (i personally have been regularly testing and treating those with low vitamin D levels for many years; the current study adds a bit of necessary oomph to this prescription)

    -- and, vitamin D repletion is cheap, safe, and easy (i do realize there are many studies on vitamin D with contradictory results, though many are really not good studies. for many prior blogs on these, see http://gmodestmedblogs.blogspot.com/search?q=vitamin+d )

geoff

 

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