Several studies have suggested that higher blood levels of vitamin D, that is, serum 25(OH)D levels, are correlated with a lower incidence of severe or critical cases of Covid-19.
As we review this research, keep in mind that vitamin D insufficiency and deficiency are a widespread problem in society, especially in the elderly and the chronically ill. See this chart from the article “Perspective: improving vitamin D status in the management of COVID-19” in European Journal of Clinical Nutrition (2020). As the evidence accumulates that low vitamin D adversely affects patients with Covid-19
1. Alipio
“Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Covid-2019 based on increasing odds ratio of having a mild outcome when serum (OH)D level increases.” [1]
One of the first studies to look at this issue was a retrospective study by Mark Alipio. He examined the medical records of 212 Covid-19 patients. They were divided into three groups by vitamin D status: (1) normal — 25(OH)D of > 30 ng/ml, (2) insufficient — 25(OH)D of 21-29 ng/ml, and (3) deficient — 25(OH)D of < 20 ng/ml. Then the patients were also divided into four categories by case severity: mild, ordinary, severe, critical. The study found that only 3.6% of persons with normal Vitamin D levels had severe or critical cases of Covid-19, whereas 79.2% of persons deficient in Vitamin D had severe or critical cases.
“Vitamin D status is significantly associated with clinical outcomes (p<0.001). A multinomial logistic regression analysis reported that the odds of having a mild clinical outcome rather than an ordinary outcome were increased approximately 1.63 times (OR=0.614, p=0.007) for each standard deviation increase in serum 25(OH)D (Table 2). Also, for each standard deviation increase in serum 25(OH)D, the odds of having a mild clinical outcome rather than a severe outcome were increased approximately 7.94 times (OR=0.126, p<0.001) while interestingly, the odds of having a mild clinical outcome rather than a critical outcome were increased approximately more than 19.61 times (OR=0.051, p<0.001)." [1]
The research above is quite compelling. I would take a vitamin D supplement based solely on that study. But there are several other studies with similar results. And since vitamin D is an essential nutrient, in which many persons are deficient, taking vitamin D supplements is a safe bet. It is very unlikely to cause harm, and fairly likely, given the current state of the research, to provide a benefits vis-à-vis Covid-19.
2. Lau
This study looked at Vitamin D Insufficiency (VDI) in patients admitted to a medical center for Covid-19.
“Among ICU subjects, 11 (84.6%) had VDI, vs. 4 (57.1%) of floor subjects. Strikingly, 100% of ICU patients less than 75 years old had VDI (n=11; Table 2). Among these, 64.6% (n=7) had critically low 25OHD (<20 ng/mL) and three had <10 ng/mL." [2]
All ICU patients less than 75 years old, who were diagnosed with Covid-19, had Vitamin D Insufficiency. And some of these admissions to ICU has incredibly low vitamin D (<10 ng/ml). This result offers a partial explanation for why Covid-19 disproportionately affects the elderly.
Then the vast majority (84.6%) of ICU patients had Vitamin D insufficiency, regardless of age, as compared to a bare majority (57.1%) of non-ICU hospital admissions. We don't have here a comparison of hospital admission to those patients sent home to self-quarantine. But if vitamin D turns out to have a large effect across all patient types, we might expect higher levels of vitamin D in those milder cases, and lower rates of VDI.
And the explanation the researchers give for these results is that Vitamin D insufficiency "induces a prothrombotic state and adversely impacts both innate and adaptive immune responses." [2] A lack of vitamin D makes thrombosis, the formation of a blood clot in a blood vessel, more likely. In addition, vitamin D is important to the proper functioning of the immune system. So high levels of vitamin D in the body keep the immune system functioning properly, which is necessary to fighting off any infection, especially one as serious as Covid-19.
3. Daneshkhah
This study cleverly used a link between C-Reactive Protein (CRP) levels and Vitamin D levels to determine that higher levels of vitamin D were correlated with a lower risk of a severe case of Covid-19. The authors attributed this reduction in severity, in part, to the effect that vitamin D has in reducing the over-reaction of the immune system called cytokine storm.
“our finding suggests that Vit D may reduce COVID-19 severity by suppressing cytokine storm in COVID-19 patients.” [3]
“Combining COVID-19 patient data and prior work on Vit D and CRP levels, we show that the risk of severe COVID-19 cases among patients with severe Vit D deficiency is 17.3% while the equivalent figure for patients with normal Vit D levels is 14.6% (a reduction of 15.6%).” [3]
A weakness of the study is that the reduction in risk of severe Covid was limited to a 15.6% lower risk. That is not as large a benefit as found in the Alipio study above [1]. This might be due in part to the imperfect relationship between CRP and vitamin D, such that the vitamin D level is not precisely known, as well as the attempt to work with nationwide data sets.
4. Davies
This study attributes differences in case fatality rate between nations to vitamin D [4]. It is well-known that nations with warmer weather and more sunshine have populations with higher levels of vitamin D (“the sunshine vitamin”). Note the mention that seasonal weather may also be a factor in Covid-19 disease statistics. Other recent studies have verified this hypothesis [5, 6].
“We analyse global data for COVID-19 deaths and recoveries and show that outbreak severity displays a striking latitude relationship with a northern hemisphere bias. Transmission rates can be explained by seasonal weather conditions, but this does not account for observed variations in fatality rates. Many factors point to Vitamin D as a candidate explanation”
The latitude relationship occurs because, at higher latitudes, summer has more daylight hours and more solar radiation per day than winter. The warm weather tends to correlate with people spending more time in the sun, with skin exposed, which raises vitamin D levels in the blood. And vitamin D is important to the immune system.
“Recent and historical data are highly consistent with a causal protective role for Vitamin D in respiratory disease risk and especially in the case of COVID-19…. Vitamin D supplementation is an effective, safe and cheap method to protect against seasonal respiratory diseases and can play a key role in combatting the COVID-19 pandemic.” [4]
The study authors (Davies, Garami, Byers) believe vitamin D should have an important role in fighting this pandemic. And they are not alone, as this article demonstrates.
5. De Smet
This study compared hospitalized patients with severe Covid-19 to a matched control group of non-hospitalized Covid-19 patients. The patients were matched so that the populations were of similar distribution by age and other factors, and by season. Since vitamin D blood levels vary by the season of the year (higher in summer, lower in winter), the controls were matched to have been ill at the same time of year.
“Findings: in this observational study on 186 consecutive patients hospitalized with PCR-confirmed SARS-CoV-2 infection, we find that patients with severe COVID-19 show lower median serum 25(OH)D and a higher percentage of vitamin D deficiency at intake than a season/age-matched reference population.”
“Meaning: our data indicate a strong statistical correlation between the degree of vitamin D deficiency and severity of COVID-19 lung disease.” [8]
The hospitalized patients were confirmed to have Covid-19 (i.e. SARS-CoV-2 infection) by a test which confirms the presence and amount of viral RNA (called PCR, for polymerase chain reaction). The hospitalized patients with more severe cases had lower vitamin D levels than diseased controls. And as the degree of severity in the hospitalized patients increased, so did the degree of vitamin D deficiency. In this study, if you had a more severe case of Covid-19, you were likely to also have a more severe vitamin D deficiency.
This study shows a correlation, not a causality; and this is a common objection to this type of study. However, it is standard methodology to establish a correlation, and, across multiple studies, to exclude various confounding factors that would explain away the correlation. This leads in the end to a conclusion that the correlation is also some type of causality.
Note that, in this study, male patients showed increasing vitamin D with increasing severity of Covid-19, while female patients did not show this correlation. For women, both the hospitalized and control groups had similar levels of vitamin D. But this fact does not undermine the relation between vitamin D and Covid-19. Rather, it offers a possible reason why women tend to have less severe cases of Covid-19 and a lower risk of death: perhaps women tend to have higher levels of vitamin D than men.
In some regions of the world, however, women have lower levels of vitamin D than men, largely because social or religious customs require them to cover their bodies. They have very little skin exposed to the sun, so they lack this major source of vitamin D. In Iran, for example, one study found that women had a higher rate of vitamin D deficiency, 55.21% in men as compared to 64.71% in women [10]. If customs cannot change, then vitamin D supplementation is a high priority.
6. Raharusun
This study found that most of those patients who died from Covid-19 had one or more of the following factors: male, older, pre-existing conditions (i.e. comorbidities), and/or below normal vitamin D blood levels [9]. Then, when they statistically excluded the other factors (sex, age, comorbidities), vitamin D status was still correlated to case fatality:
“When controlling for age, sex, and comorbidity, Vitamin D status is strongly associated with COVID-19 mortality outcome of cases.” [9]
This study divided vitamin D levels into three groups: deficiency at <20 ng/ml; insufficiency at 21 to 29 ng/ml; normal at 30 ng/ml or higher. This is a common classification for vitamin D.
In this study, located in Indonesia, "98.9% of Vitamin D deficient cases died…. 87.8% of Vitamin D insufficient cases died…. Only 4.1% of cases with normal Vitamin D levels died." [9] This is a striking difference, which might be due, in part, to the level of health care available to the entire group of patients. In developed nations, such a high death rate is not seen, even with old age, co-morbidities, and lower vitamin D. Even so, notice that those with sufficient levels of vitamin D had a comparatively low rate of death.
For any nation, region, or population that lacks sufficient health care resources, high levels of vitamin D can be obtained from exposing skin to sunlight. This remedy is free, and the protective effect in the face of a deadly pandemic is remarkably strong. What other treatment can be provided to the billions of persons in the world who live on a few dollars a day?
“Females (51.3%) outnumbered males (48.7%); however, there were more male cases who died (66.6%) than female (33.4%).” [9]
This gender difference has been seen in many studies. Men tend to be twice as likely to die than women. In New York City, for example, men accounted for 61.8% of deaths; women, 38.2% [11]. The gender difference does not seem to be explained by vitamin D. However, vitamin D does reduce risk of Covid-19 mortality for men, more so than for women [8]. This greater reduction may be due to the higher rates of severity and mortality for men — there is more to be reduced.
To Be Continued
The above six studies offer compelling results. And yet there are several more studies to be considered. In addition, over a dozen authors or groups have written opinion pieces evaluating those studies. The consensus is building that vitamin D should be used to protect the population from Covid-19. Part two of this series will examine the other studies. Part three will review the commentaries written by experts on these studies.
Ronald L Conte Jr
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.
1. Alipio, Mark. “Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19).” SSRN 3571484 (9 April 2020).
2. Lau, Frank H., et al. “Vitamin D insufficiency is prevalent in severe COVID-19.” medRxiv (28 April 2020).
3. Daneshkhah, Ali, et al. “The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients.” medRxiv (2020).
4. Davies, Gareth, Attila R. Garami, and Joanna C. Byers. “Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes.” medRxiv (2020).
5. Qin, Lei, et al. “The Effect of Temperature and Humidity May Reduce the Growth Rate of the Coronavirus Disease 2019 Epidemic.” (2020).
6. Sethwala, Anver, et al. “The effect of ambient temperature on worldwide COVID-19 cases and deaths-an epidemiological study.” medRxiv (2020).
7. Ebadi, Maryam, and Aldo J. Montano-Loza. “Perspective: improving vitamin D status in the management of COVID-19.” European Journal of Clinical Nutrition (2020): 1-4.
8. De Smet, Dieter, et al. “Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics.” medRxiv (2020).
9. Raharusun, Prabowo, et al. “Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study.” (2020).
10. Tabrizi, Reza, et al. “High prevalence of vitamin d deficiency among iranian population: A systematic review and meta-analysis.” Iranian journal of medical sciences 43.2 (2018): 125.
11. Worldometers.info; “Age, Sex, Existing Conditions of COVID-19 Cases and Deaths.”
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