COVID: high vit D prior to covid improves outcomes
A new Israeli study found a dramatic clinical benefit of adequate vitamin D levels before a Covid infection (see covid vit d preinfection dec severity plos2022 in dropbox, or doi.org/10.1371/journal.pone.0263069 ). Thanks to Paul Ash for bringing this to my attention
Details:
-- 253 of 1176 patients admitted to the Galilee Medical Center between April 7, 2020 and February 4, 2021 had a vitamin D level [25(OH)D] assessed prior to a documented Covid 19 infection by 14-730 days, in this retrospective study [the minimum of 14 days would exclude having an early covid infection]
-- mean age 63, 57% women
-- comorbidities: COPD 45-62%, heart failure 5-12%, CAD 3-12%, CKD 8-13%, diabetes 33-42%, hypertension 45-62% (the low range of all of these diseases was in those with the highest vitamin D level)
-- vitamin D levels were stratified as deficient (<50 nmol/L or 20 ng/mL), insufficient (50-75 nmol/L or 20-30 ng/mL), adequate (75-100 nmol/L or 30-40 ng/mL), or high normal (>100 nmol/L or >40 ng/mL)
-- in the study, 53% had the lowest level of vitamin D (deficient), 14% (insufficient), 17% (adequate), and 16% (high normal)
-- a mathematical model was developed to equalize the typical sinusoidal pattern of seasonal 25(OH)D changes throughout the year, with the results noted below indicating the actual measured 25(OH)D level in patients prior to the Covid infection, that number mathematically corrected for the seasonal variation by the hospitalization month, and that number mathematically corrected for the annual mean 25(OH)D value
Results:
-- Covid disease severity, per measured 25(OH)D values before hospitalization:
-- 25(OH)D <20: mild disease 5%/moderate disease 38%/severe disease 48%/critical 9%
-- 25(OH)D 20-30: mild disease 22%/moderate 67%/severe 8%/critical 3%
-- 25(OH)D 30-40: mild disease 84%/moderate 7%/severe 9%/critical 0
-- 25(OH)D >40: mild disease 70%/moderate 23%/severe 8%/critical 0
-- in all models, about 48% of vitamin D deficient patients had severe disease versus <10% of patients with 25(OH)D >20
-- a deficient vitamin D level was more common in patients with severe or critical disease (87.4%) than in those with mild or moderate disease (34.3%), p <0.001
-- here is their summary table assessing the relationship between vitamin D levels and severity of Covid disease, comparing severe or critical versus mild or moderate disease
-- notable findings included:
-- age was also an independent risk factor for severe Covid, with more severe cases in older people as well as those who were diabetic and had COPD
-- though pre-infection vitamin D levels and age were independent predictors of Covid severity, those who were older had lower vitamin D levels: those <50 years old still had a highly significant relationship between 25(OH)D and disease severity (p<0.001), though this relationship was less profound than in those >65yo (see graph below for differences by age)
Commentary:
-- vitamin D receptors are relatively omnipresent throughout the body, with large numbers in the immune system (both innate and adaptive). There is an array of important specific immunologic effects of vitamin D sufficiency (see http://gmodestmedblogs.blogspot.com/2020/05/covid-vitamin-d-deficiency-may-lead-to.html for a detailed review of the effects of vitamin D on the immune system and clinical outcomes). But for example vitamin D inhibits the production of pro-inflammatory cytokines (including TNF-alpha and IL-6) and down regulates viral-induced NFkB activation. And such inflammatory cytokines are associated with "cytokine storm", a potentially very serious outcome
-- Covid epidemiologic studies have suggested that there is worse covid prognosis in those in northern countries (less sunlight), older people, those with darker skin pigmentation, and obesity, all of which are associated with lower vitamin D levels
-- several studies (but not all), including the ones noted at the end of this blog, have found that low vitamin D levels are associated with increased covid disease severity and worse clinical outcomes, eg see Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers | Scientific Reports (nature.com)
-- Though the overall results did not vary hugely between the different ways of assessing 25(OH)D levels in this study, it does seem that the most appropriate comparisons for the effect of vitamin D on Covid severity would be the vitamin D level prior to hospitalization but corrected for monthly variation, thereby adjusting the patients' measured 25(OH)D to a single standard of measurement, independent of the time of the year
-- Given the multiple inputs for covid disease severity (age, comorbidities, sociodemographics, etc), it is quite remarkable that the odds ratio revealed about a 14-fold difference between those with insufficient versus high normal 25(OH)D levels in all of their analyses
-- one real advantage of having pre-disease vitamin D levels is that there might be real differences in measured 25(OH)D in those with active Covid infection: a small study found that systemic inflammation lowered the 25(OH)D in humans (see https://www.metabolismjournal.com/action/showPdf?pii=S0026-0495%2820%2930298-5 ).
-- It is unclear exactly what the sufficient 25(OH)D level really is. The various guidelines suggest either >20 ng/mL or >30 ng/mL, which is based on the assessment of what is necessary for bone and muscle health, typically measured as the risk for fractures and falls. Some studies have looked at PTH levels which vary inversely with 25(OH)D levels. However, this is inexact. And observational studies for cancer over the decades have suggested that vitamin D levels needed to be much higher to be associated with decreased cancer incidence, such as >40 ng/mL. But there is really no evidence-based understanding of what the sufficient level is for the whole body, and it may be very different for bone versus immune function.
-- it was found in the table above that the only individual cutpoints of 25(OH)D with statistical significance was if the 25(OH)D level was <20 ng/mL vs >40 ng/mL, associated with huge increase in covid severity. the other 25(OH)D levels were not so different from each other when compared to >40 ng/mL. But the above graph stratified by age did find a significant linear relationship between 25(OH)D and covid severity for each age group, with that linear relationship being highly significant, with p<0.001
Limitations:
-- this was a retrospective and not a systematic study. Only 22% of the patients had vitamin D levels checked prior to their Covid infection. Why did these people have vitamin D levels checked? Were they different in important ways versus those who did not have vitamin D levels checked? If so, that would limit generalizability of the results
-- Higher vitamin D levels may be a marker of other healthful behaviors: going outside to get more exercise, perhaps eating more foods that have high vitamin D levels (fish, fortified orange juice or dairy), perhaps taking vitamin D supplementation that might also be associated with other healthy supplements. We have none of this information in this study
-- in fact, the mathematical model they are using involves a generic model of predicted 25(OH)D levels by month of the year. not even from Galilee. and, though this does reflect the reality of 25(OH)D level differences in some area, does it truly reflect Galilee? it is not just the quantity of light but also its intensity. For example, in Boston in the winter on a bright and sunny day, the sun is at such an angle that there is minimal UVB light that penetrates the atmosphere and can reach the skin (also we have less exposed skin in the winter) to create vitamin D. and, of course, the quantity of vitamin D in the blood would also reflect people taking supplements or megavitamins, which would presumably even out the vitamin D level differential of winter/summer. so, it is likely that this mathematical modeling in the study was actually really useful, but we do not have enough info to be certain
-- there is also a clear interaction between vitamin D levels and age (there is decreased vitamin D conversion by sunlight with aging), or obesity (which similarly decreases vitamin D levels). and these types of interactions may be important ones that cannot be simply factored out by mathematical adjustment (especially in a small study such as this one): eg, obesity may well decrease the production of vitamin D by sunlight (leading to lower 25(OH)D levels), but also that SARS-CoV-2 virus can infect adipose tissue itself and elicit an inflammatory response, as is found in severe Covid (see covid obesity mechanism biomedrx2021 in dropbox, or doi: https://doi.org/10.1101/2021.10.24.465626). the issue here is that we can not necessarily assume that the risk factors are independent and can easily be controlled for mathematically, since they may have significant interactions with each other, and perhaps with multiple others. And, one could even have a scenario where a potential risk factor by itself poses no increased risk, but in combination with one or more others can be a powerful enabler. so, just a warning about some of the limits of mathematical multivariable adjustments
-- would be interesting to know what the relationship with vitamin D and covid was for asymptomatic people, since they do not have the dramatic immunologic/inflammatory response to SARS-CoV-2. do they have high 25(OH)D levels which protect them? or does vitamin D not even come into play since other factors are protecting asymptomatic people from symptomatic infection?
-- was there a selection bias in which covid patients were admitted to this hospital? seems that lots were admitted with mild to moderate infections. but was their admission group reflective of the array of covid infection severity in the community? if not, that would limit generalizability to the general population
So, a really well-done study. We do know well that 25(OH)D levels vary dramatically dependent on exposure to and intensity of sunlight, which varies seasonally in much of the world. Most prior studies on vitamin D have relied on a single value of 25(OH)D, or have a vitamin D level measured during some adverse event (eg hospital admission for an infectious illness). This study has the benefit of vitamin D values prior to illness as well as values corrected by the month of hospitalization to allow some standardization and comparison. And, there was that really dramatic 14-fold difference in those with low vs high 25(OH)D levels.
And, as an aside, i have been impressed for several decades with the diverse potential roles of vitamin D in the human body, both by older epidemiologic studies (differences in many diseases in northern latitudes vs southern ones) as well as the fact that vitamin D receptors are pretty omnipresent in the body. Also much of early human evolution was in the highly sunny fertile crescent (where there was no evolutionary need to develop the ability to synthesize vitamin D other than from the sun). So, in the northern clime of Boston, i have been regularly checking patients' 25(OH)D levels, finding that deficiency was the norm (with several patients having essentially undetectable levels), and that levels >30 ng/mL were very unusual. So, for what it's worth, the large majority of my patients are on vitamin D supplements (including myself)..... And the risk of too much vitamin D is really minimal
Here are some relevant prior vitamin D blogs:
-- http://gmodestmedblogs.blogspot.com/2020/05/covid-vitamin-d-deficiency-may-lead-to.html , which reviews an international study finding that those with likely vitamin D deficiency had a higher risk of severe Covid, and a much more detailed review of the effects of vitamin D on the immune system
-- http://gmodestmedblogs.blogspot.com/2020/10/covid-vit-d-sufficiency-dec-risk.html , an Iranian study which found that vitamin D sufficiency was associated with lowering CRP levels as well as decreased disease severity
-- and, for those really interested in vitamin D, including articles on its relationship with cognitive impairment, cancer risk, osteoporosis, acute respiratory illness, migraine prophylaxis, atopic dermatitis, etc, see http://gmodestmedblogs.blogspot.com/search?q=vitamin+d
geoff
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