|Year : 2020 | Volume
| Issue : 4 | Page : 229-234
Coronavirus Disease 2019 (COVID-19) and Vitamin D Status: Is there any Opportunity for Intervention?
Rizaldy Taslim Pinzon1, Winny Frida2, Vincent Ongko Wijaya1, Dessy Paramitha1, Patrick Nalla Nunsio1, Abraham Al Jody1
1 Duta Wacana Christian University School of Medicine, Yogyakarta; Bethesda Hospital, Yogyakarta, Indonesia
2 Bethesda Hospital, Yogyakarta, Indonesia
|Date of Submission||03-Jun-2020|
|Date of Decision||07-Jun-2020|
|Date of Acceptance||02-Jul-2020|
|Date of Web Publication||01-Oct-2020|
Vincent Ongko Wijaya
Faculty of Medicine Duta Wacana Christian University, Dr. Wahidin Sudirohusodo Street Number 5-25, Yogyakarta 55224
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Aim: Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease that has affected every aspect of life in many countries. Previous studies suggested that the role of vitamin D in the immune system has certain significances in managing COVID-19 patients. This study aims to report the level of vitamin D in COVID-19 patients. Methods: We collected a series of confirmed cases from period of March through May 2020. The data collected including clinical symptoms, clinical signs, and laboratory examinations from 10 COVID-19 patients in Bethesda Hospital, Yogyakarta, Indonesia. This study used ELFA (enzyme-linked fluorescent assay) to measure vitamin D levels in serum or plasma. The collected data was analysed descriptively. Results: This study examined 10 patients with mean age of 49.6, ranging from 14 to 73 years old and most common age group was <60 years (60%). The gender ratio was equal between men and women (50:50). Most common symptoms were fatigue (60%) and fever (50%), whereas hypertension (40%) was the most common comorbidity. Most of patients (90%) had vitamin D deficiency (<20 ng/mL) and only 1 patient (10%) had insufficient vitamin D levels (<30 ng/mL). Conclusion: All of the COVID-19 patients in this study had suffered a decreased vitamin D levels, and more common in non-elderly patients. This is a novel findings of vitamin D deficiency in COVID-19 and has not been reported yet. Physicians should be aware in managing COVID-19 patients, especially the risk of vitamin D deficiency.
Keywords: COVID-19, deficiency, vitamin D
|How to cite this article:|
Pinzon RT, Frida W, Wijaya VO, Paramitha D, Nunsio PN, Jody AA. Coronavirus Disease 2019 (COVID-19) and Vitamin D Status: Is there any Opportunity for Intervention?. Int J Nutr Pharmacol Neurol Dis 2020;10:229-34
|How to cite this URL:|
Pinzon RT, Frida W, Wijaya VO, Paramitha D, Nunsio PN, Jody AA. Coronavirus Disease 2019 (COVID-19) and Vitamin D Status: Is there any Opportunity for Intervention?. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2021 Jan 19];10:229-34. Available from: https://www.ijnpnd.com/text.asp?2020/10/4/229/297507
| Background|| |
The world is now facing a global outbreak of COVID-19 that imposed catastrophic impacts on every society. The new coronavirus infection pandemic began in Wuhan, China, in late 2019. Currently, there are no approved treatment or vaccine yet. There is an urgent need to elucidate potential approaches that can reduce the number of severe COVID-19 cases. Those approaches must be able to reduce the mortality rate of the disease. Previous studies had proposed that the immune system has potential role that could produce better outcomes in some COVID-19 patients.,
The data from Indonesian COVID-19 Task Force as of May 7, 2020, showed that there were 12.438 confirmed cases, 26.932 active suspected cases, and 895 confirmed death (7.2%). The COVID-19 mortality rate of Indonesia is the highest among Southeast Asian countries.
Indonesia is a tropical country with abundant sunray exposure, as it lies within the equatorial zone. Previous study showed that the prevalence of 25(OH)D deficiency among Indonesian elderly women in institutionalized care is about 35.1%. Recent study from Indonesia showed that prevalence of vitamin D deficiency was 23.0%.
Data concerning the role of vitamin D in supporting the immune system were obtained from previous studies., Vitamin D can simultaneously suppress cytokine production and boost the innate immune system and also regulates adaptive immune system. Murdaca et al. suggested that vitamin D is able to complement the innate immune system by the release of cathelicidins. Cathelicidins bind to microbes to eradicate them. The release of cathelicidins succeeds the activation of 25-hydroxyvitamin D-1α-hydroxylase, which is responsible for the releasing of the aforementioned cathelicidins. Another subtype of vitamin D, cholecalciferol, has positive effect to the activity of dendritic cells, which translates to decreased IL-12 production and inhibited monocyte differentiation. Regarding adaptive immune system, vitamin D may inhibit B-cell proliferation and differentiation, promoting their apoptosis, and, finally, decreasing immunoglobulin production, including antibodies. Vitamin D also may inhibit the secretion of proinflammatory Th1 (IL-2, interferon-γ, tumor necrosis factor α), Th9 (IL-9), and Th22 (IL-22) cytokines and promotes the production of more anti-inflammatory Th2 cytokines (IL-3, IL-4, IL-5, IL-10). These findings may explain the protective effect of vitamin D upon the risk of developing inflammatory disease.
The ability of vitamin D to suppress cytokine production inspired a recent study to test the vitamin D deficiency and its association with severe COVID-19. No randomized controlled blinded trial has yet reported the benefit of vitamin D supplementation, vitamin D status, and cytokine levels in patients with COVID-19. The hypothetical evidence suggested that the association between vitamin D status and severe COVID-19 is based on a potential link between vitamin D deficiency and C-reactive proteins (CRP), this study suggests possible role of Vit D in reducing complications attributed to unregulated inflammation and cytokine storm. The examination of vitamin D status is not a routine in Indonesian clinical setting. The aim of our study was to report a case series of vitamin D status in patients with confirmed COVID-19. To complement our study, we also reviewed recent literatures on the role of vitamin D on COVID-19.
| Methods|| |
This study used case series from confirmed cases of COVID-19 in Bethesda Hospital, Yogyakarta, Indonesia. All the patients had either positive serology or real-time PCR (polymerase chain reaction) for COVID-19, and the specimens were collected from nasopharyngeal or throat swab. Patients with pre-existing liver or renal impairment/disease were not included in this study.
The patients had also given the consent to participate in this study. Patients were enrolled consecutively and the data was collected based on clinical symptoms, clinical signs, and laboratory examinations. The data were obtained from electronic medical record of each patient. We analysed the data using descriptive analysis. This study obtained ethical clearance and permission from Bethesda Hospital, Yogyakarta, Indonesia.
The vitamin D status was measured by standardized laboratory methods. The vitamin D examination used VIDAS® 25OH Vitamin D (bioMérieux Marcy l’Etoile) for vitamin D2, and Enzyme-linked Fluorescence Assay for vitamin D3. We used enzyme immunoassays for the quantitative measurement of total serum 25(OH) vitamin D levels or 25(OH)D. We used the standard parameter of vitamin D, as following (ng/ml): <20 for deficient, 20–29 for insufficient, 30–100 for sufficient, and >100 for potential toxicity.
There were no study explained the reference range of vitamin D levels based on age. However, past study reported gender and age has little influence on 25(OH)D concentrations. A recent systematic review found that serum 25(OH)D level above 30 ng/ml is considered optimal and has been widely accepted.,
We conducted literature research regarding the benefit of vitamin D in COVID-19 using PubMed and Google Scholar. The clinical question is “Is there any benefit of vitamin D treatment in patients with COVID-19?” We did not find any trials of vitamin D in COVID-19. Although, we did find several studies that are registered, but have not yet reported. None seemed to be masked comparisons to placebo.
| Results|| |
Demographic and clinical characteristics
During the period of March through May 2020, we identified 10 patients with confirmed COVID-19 infection in Bethesda Hospital. All the patients had either positive serology or real-time PCR for COVID-19. [Table 1] shows the demographic and main clinical characteristics of the patients. The patients’ age range from 17 to 73 years old, with mean age of 49.6. The proportion of male and female patients was equal. Two patients (20%; patient 3 and 7) had no symptoms at admission, while the rest (80%) had symptoms ranging from fatigue (60%), fever (50%), dry cough (40%), headache (20%), and diarrhoea (10%). None of the patients had recently travelled to a country with known high-level infection rate, such as China, South Korea, Iran, or Italy. Thirty percent of the patients have close contact with confirmed COVID-19 patients. Five patients (50%) had comorbidity(s), whereas two of them had more than one comorbidity. Hypertension was the most commonly found comorbidity in this study (40%).
[Table 2] shows the laboratory findings in the patients on admission in our hospital. From the laboratory findings, most of the result were still in the normal range. Four patients (40%) had an increased segmented neutrophil count, while it was not significant. Lymphocytopenia, which is one of the typical findings in a viral infection, only occurred in three patients (30%; patient 2, 8, and 10). An increase in platelet count, which is rare in viral infection, occurred in two patients (20%; patient 1 and 5).
The diagnostic serological tests for COVID-19 showed that six patients (60%) had reactive IgM. Two out of the six patients did not have reactive IgG on admission in our hospital.
From the laboratory findings, patient 2 had high blood glucose levels (384.5mg/dl). This result is in accordance with diabetes mellitus comorbidity of the patient. This patient also had elevated liver enzyme, with no previous history of liver disease before admission.
Vitamin D profile
The majority of patients (90%) had vitamin D deficiency. We also found that only one patient (male, 17 years old) who had insufficient vitamin D levels, and the rest of the patients did not have sufficient vitamin D level [Table 3]. Lowest vitamin D levels occurred in three patients, which included a 74-year-old male and the females, age 49 and 56 years old, with vitamin D levels below 8 ng/ml [Table 2]. As previously known, decreased vitamin D levels is more common in female and elderly people.
| Discussion|| |
Our study showed that all patients have deficient or insufficient status of vitamin D. Some of the patients have very severe deficiency. This finding is in contrast to the fact that Indonesia is a tropical country with abundant sun-exposure, therefore vitamin D deficiency from sun exposure may be uncommon. Diet was also considered as one of the source for vitamin D, yet it is difficult to assess dietary status intake from our patients.
Previous report have speculated that people with low serum vitamin D might be at higher risk of infection with COVID-19, or will be worsen when infected. There is an overlap between groups at high risk of vitamin D deficiency and groups at high risk of severe COVID-19. Examples include people with chronic disease and elder people. Our studies showed that half of the COVID-19 cases were found in with chronic disease(s) (e.g. hypertension).
One patient had elevated liver enzyme after admission, which can be caused from COVID-19 injury to the liver organ. Liver or renal damage may impair vitamin D regulation in the body, thus leading to inadequate production of active vitamin D or 1,25(OH)2D and may lead to hypocalcemia. In our patient relationship between liver injury and vitamin D deficiency, remains unclear. However, vitamin D deficiency alongside with liver injury may worsen the decrease vitamin D levels.
We found no trials of vitamin D in COVID-19 that have reported results. We did find several studies that are registered, but not yet reported. None seemed to be masked comparison to placebo. A trial of vitamin D3 plus zinc versus usual care is planned in an open-label randomised controlled trial (RCT) in adults over the age of 60 years who are ‘institutionalized’ but asymptomatic. The primary outcome measure is mortality; the incidence of COVID-19 infection is a secondary outcome.
One trial is conducting tests whether a single oral dose of 25,000 IU (25 μg) of vitamin D would improve mortality in patients who are infected with SARS-CoV-2, but do not have severe symptoms, compared with usual care. Another RCT is comparing single doses of vitamin D3, 50,000 IU to 200,000 IU (1,250 to 5,000 μg) in people with COVID-19-associated pneumonia who are over 75 year old or over 70 year old with low oxygen saturations; the primary outcome measure is mortality at 14 days.
Review and meta-analysis of RCTs have suggested a protective effect of vitamin D3 supplementation taken over weeks to months. This was more pronounced in patients with the lowest baseline concentration of vitamin D. Through several mechanisms, vitamin D could reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation. A recent review suggested recommendation as follow: to reduce risk of infection, it is recommended that people who at risk of influenza and/or COVID-19 to consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5,000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/ml (100–150 nmol/l). For treatment of COVID-19 patients, higher vitamin D doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
Our study showed that elderly and female tends to have lower vitamin D status. This is relevant with the facts on vitamin D and COVID-19. Serum 25(OH)D concentrations tend to decrease with age. In COVID-19 cases, the case-fatality rate (CFR) increase with age. Owing to the lack of specific treatment and urgency to act, these findings could be tentatively extrapolated to the use of vitamin D as a possible adjuvant therapy. Given the good tolerability and safety of even high doses of vitamin D.We found no high-quality clinical evidence that vitamin D supplements are beneficial in preventing or treating COVID-19. There is some evidence that vitamin D may have a role in preventing other respiratory infections, particularly for people with low or very low vitamin D status. Whilst this evidence comes from systematic reviews of randomised trials, it has many limitations, including heterogeneous definitions of respiratory infections, study populations, interventions and definitions of vitamin D deficiency.
Evidence from well-masked randomized trials was required to determine if there are effects, before recommending vitamin D3 supplements for treating or preventing COVID-19 infection. The hypothesis that vitamin D supplementation can reduce the risk of influenza and COVID-19 incidence and death should be investigated in trials to determine the appropriate doses, serum 25(OH)D concentrations, and the presence of any safety issues.
People at risk of vitamin D deficiency should in any case take supplements in line with current guidance. In our case series, we treated our entire patients with 2,000 IU oral supplementation. The follow-up for the treatment was not included in this study, hence this is one of our study limitation which we don’t have any data of previous or baseline vitamin D levels, therefore we cannot measured whether the vitamin D deficiency was before or after admission. As clinicians, we should continue to aware of people with vitamin D deficiency, but not because of any possible association with respiratory infection.
| Conclusion|| |
All of the COVID-19 patients in this study had suffered a decreased vitamin D level, whether it is a deficiency or insufficiency. Our study has several limitations. First, this study has a small sample size. A larger sample size would make future studies more significant. Second, we did not follow up the patients concerning the clinical aspects or the vitamin D level. Conducting follow up to the patients would benefit in a more thorough observation on the patients’ clinical course.
While the current knowledge on vitamin D role in COVID-19 may be limited, future studies are expected to discover the role of vitamin D in treating COVID-19 patients, especially in the form of clinical trials. We hope that our study able to suggest physicians to consider this approach in managing COVID-19 patients
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X et al.
A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020.
Yao H, Lu X, Chen Q, Xu K, Chen Y, Cheng L, Liu F, Wu Z, Wu H, Jin C, Zheng M, Wu N, Jiang C, Li L. Patient-derived mutations impact pathogenicity of SARS-CoV-2, MedRxiv. (2020) 2020 .04. 14. 20060160. https://doi.org/10.1101/2020.04.14.20060160
Dowd JB, Andriano L., Brazel D.M., Rotondi V., Block P., Ding X., Liu Y., Mills M.C., Demographic science aids in understanding the spread and fatality rates of COVID-19. Proc Natl Acad Sci 2020. https://doi.org/10.1073/pnas.2004911117
Setiati S. Vitamin D status among Indonesian elderly women living in institutionalized care units. Acta Med Indonesia 2008;40:78-83.
Prabowo R., Sadiah P, Cahni B, Erdie A, Cipta B. Patterns of COVID-19 mortality and Vitamin D: An Indonesian Study (April 26, 2020). Available at SSRN: https://ssrn.com/abstract=3585561
Daneshkhah A, Agrawal V, Eshein A, Subramanian H, Roy H, Backman V. The possible role of Vitamin D in suppressing cytokine storm and associated mortality in COVID-19 Patients, medRxiv. 2020. 04.08.20058578; doi:https://doi.org/10.1101/2020.04.08
Murdaca G, Tonacci A, Negrini S et al.
Emerging role of vitamin D in autoimmune diseases: an update on evidence and therapeutic implications. Autoimmun Rev 2019;18:102350. doi:10.1016/j.autrev.2019.102350
Li Q, Dai Z, Cao Y, Wang L. Association of C-reactive protein and vitamin D deficiency with cardiovascular disease: a nationwide cross-sectional study from National Health and Nutrition Examination Survey 2007 to 2008. Clin Cardiol 2019;42:663-9. https://doi.org/10.1002/clc.23189
Selvarajan S, Gunaseelan V, Anandabaskar N et al.
Systematic review on Vitamin D level in apparently healthy indian population and analysis of its associated factors. Indian J Endocrinol Metab 2017;21:765‐75. doi:10.4103/ijem.IJEM_168_17
Vuistiner P, Rousson V, Henry H, Lescuyer P, Boulat O, Gaspoz J et al.
A population-based model to consider the effect of seasonal variation on serum 25(OH)D and vitamin D status. BioMed Res Int 2015;2015:168189. 10.1155/2015/168189
Bergman P, Lindh ÅU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One 2013;8.
Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, Bhattoa HP. Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020;12:988.
Vasarhelyi B, Satori A, Olajos F, Szabo A, Beko G. Low vitamin D levels among patients at Semmelweis University: retrospective analysis during a one-year period. Orv Hetil 2011;152:1272-7.
Novel CPERE. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing XueZaZhi 2020;41:145-51.
Jakovac H. COVID-19 and vitamin D—is there a link and an opportunity for intervention? American Journal of Physiology-Endocrinology and Metabolism 2020;318:5, E589-E589.
[Table 1], [Table 2], [Table 3]