COVID: vitamin D seems to decrease disease severity

 A recent Spanish study found that vitamin D given to hospitalized patients was associated with significantly decreased ICU admissions and mortality, in a preprint pre-peer reviewed article (see covid vit d decreases ICU and mortality lancet2021 in dropbox, or https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3771318# ) 

 

Details: 

-- 930 patients who were admitted with Covid-19 in Barcelona, 551 randomized to vitamin D3 in the form of calcifediol vs 379 controls 

    -- patients were given 532 µg (21,280 IU) of vitamin D on day 1 of hospital admission and 266 µg (10,640 IU) on days 3, 7, 15, and 30 

-- 56% male, mean age 63, 86% white/8% Asian 

-- baseline 25(OH)D was 15 ng/mL in the treated group vs 12 ng/mL in the nontreated group (p<0.001); of these, 66% had levels <20 ng/mL: 55% in the treated group and 50% in the untreated [these numbers do not exactly match up, which happens in these pre-print publications]

-- other factors were equivalent, including hypertension in 46%, dyslipidemia 30%, CAD 20%, obesity 8%, cancer 9%, chronic kidney disease 8%, chronic infections 4%, chronic respiratory diseases 20%, diabetes 20% 

-- all patients were at least 18 years old, were PCR-positive for SARS-CoV-2, and had chronic conditions and/or severe Covid-19 symptomatology (not defined)

-- all patients received the standard therapy at the time: hydroxychloroquine 400 mg the 1^st day then 200 mg for 4 days, azithromycin 500 mg for 3 days, and ceftriaxone 1-2 g a day for 7 days. Dexamethasone was added in those with evidence of severe or critical pulmonary inflammation or suspicion of cytokine storm. This study was based on the 1^st European outbreak of Covid 

-- vitamin D sufficiency was defined as at least 20 ng/mL 

  

Results: 

-- ICU transfer (110 patients overall):  

    --those admitted to ICU had lower 25(OH)D level than those remaining on the ward (11 vs 15 ng/mL) 

        -- baseline 25(OH)D levels were inversely correlated with risk of ICU admission, RR 0.53 (0.35-0.80)  

            -- those with baseline 25(OH)D levels >20ng/mL had 55% fewer ICU admissions, RR 0.45 (0.24-0.84), p=0.013 

    --ICU transfers: 30 patients (5.4%) on vitamin D vs 80 control patients (21.1%), p<0.0001  

        --adjusting for age, gender, 25(OH) D level at baseline, and comorbidities: 82% decreased risk of ICU admission, RR 0.18 (0.11-0.29) 

    -- obesity was also significantly associated with ICU admission, with OR 2.55 (1.29-5.04), which did not vary significantly by baseline 25(OH)D status 

     

-- mortality: 

   -- overall mortality 10% 

    -- death rate: 

        -- 36 (6.5%) of those treated with vitamin D vs 57 (15%) of controls died, p=0.001 

        -- adjusted mortality showed a 64% decrease, RR 0.36 (0.19-0.67), by intention-to-treat analysis.

        -- 50 patients started vitamin D while in the ICU: not significantly different mortality from the group never started 

 

Commentary: 

-- this study found that administering vitamin D at the time of Covid hospital admission led to a 64% decrease in mortality, and that baseline 25(OH)D levels correlated negatively with ICU admission and mortality, though there was benefit as well in those with 25(OH)D levels >20 ng/mL

-- several prior observational studies have found that adequate vitamin D status was associated with fewer SARS-CoV-2 infections, lower levels of pro-inflammatory cytokines, decreased disease progression, and lower mortality. But, the question comes up with observational studies: were there other unappreciated confounding factors, such as those who had adequate vitamin D levels might be taking care of themselves better overall, perhaps getting more exercise outdoors, perhaps eating better, ... 

-- there was also a small randomized pilot study in Córdoba, Spain of 76 patients, finding similar results to the above study, with a 50% decreased mortality in the vitamin D supplemented group (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456194/ ) 

-- in the current study they used calcifediol, an analog of 25(OH)D₃, felt to have a higher bioavailability (higher intestinal absorption), as well as not requiring hepatic hydroxylation and perhaps therefore easier to convert to the active 1,25(OH)₂D (hepatic function might be impaired in some Covid patients). [Though I must admit that I’d never heard of calcifediol before] 

-- interesting that those with “sufficient” vitamin D levels still showed benefit, with a 55% reduction in ICU admission. This attests to the fact that we do not really know what vitamin D level is actually sufficient for the different potential vitamin D benefits. It does appear a level in the 20 to 30 range is adequate for suppressing PTH levels, thereby presumably decreasing bone absorption/osteoporosis. However, we do not know clinically what the appropriate vitamin D level is for other bodily functions. For example, from observational studies it seems that vitamin D levels in the 40 to 50 ng/mL range are associated with cancer prevention. Unclear what levels are needed for full immunologic functioning 

    -- there are vitamin D receptors throughout the body, including in the immune system. Vitamin D is important for the adaptive immune system in modifying the phenotype of the dendritic cells that present antigens to the T cells, leading to a decrease in pro-inflammatory T cell subtype proliferation and enhancing the production of regulatory T cells. Also, pro-inflammatory cytokines released in macrophages are also decreased by vitamin D supplementation. So overall, there is a significant decrease in cytokine release (which likely explains the lower CRP levels found by vitamin D repletion). And there is even an immunologic argument that vitamin D might prevent Covid infection. The results of clinical studies however are mixed on the immune system effects of vitamin D (see https://www.thelancet.com/article/S2352-3964(18)30141-5/pdf ) 

       --eg, a recent observational study found that patients who were vitamin D sufficient were found to have lower CRP levels and reduction in Covid clinical severity (see covid vit d reduces adverse outcomes PLoS2020 in dropbox, or doi.org/10.1371/journal.pone.0239799; or, see http://gmodestmedblogs.blogspot.com/2020/10/covid-vit-d-sufficiency-dec-risk.html  

    -- I would argue, however, that it is a tad reductionist to think that a single intervention such as repleting vitamin D levels, will in-and-of-itself dramatically alter disease course. The development and trajectory of disease is undoubtedly influenced by many factors, and the fact that vitamin D has such impressive effects on the immune system suggests that "adequate" vitamin D levels are likely an important part of the immune response in conjunction with other healthful behaviors/meds/etc (for more info on the immunological effects of vitamin D, as well as reference to a study finding that those with active TB randomized to vitamin D repletion had a more rapid response to anti-TB meds:  http://gmodestmedblogs.blogspot.com/2020/05/covid-vitamin-d-deficiency-may-lead-to.html 

 

Limitations: 

-- this was not a placebo-controlled trial; therefore, clinicians knew which patients were getting vitamin D and may have conceivably treated those patients differently, altering outcomes. However, the huge differences in outcomes would make that unlikely 

-- they have no data on the achieved vitamin D levels, though these were likely pretty high given the large doses of vitamin D administered

-- the population studied had a low vitamin D level at baseline, so the results may not be generalizable to populations with much higher baseline vitamin D levels 

 

So, this study adds to the potential utility of vitamin D, which is reinforced by: 

-- the fact that vitamin D levels are very low in most northern climes, including Boston (and, apparently, Barcelona)

-- the fact that vitamin D receptors are on pretty much all human cells, including those involved in immune response; and there is a strong argument in the literature that these immune responses improve with adequate vitamin D levels 

-- vitamin D is really quite cheap and plentiful, a remarkably insignificant cost compared to pretty much anything else done in the hospital (especially ICU care) 

-- so, why not give it???? and perhaps replete it even before a covid-19 infection??

geoff

 

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