key: cord-1025299-9g47ga93
authors: da Rocha, Aline Pereira; Atallah, Alvaro Nagib; Aldrighi, José Mendes; Pires, Andréa Larissa Ribeiro; dos Santos Puga, Maria Eduarda; Pinto, Ana Carolina Pereira Nunes
title: Insufficient evidence for vitamin D use in COVID‐19: A rapid systematic review
date: 2021-08-18
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14649
sha: 20dce9dbf5d8215ba734fc8653591cd28e13eec4
doc_id: 1025299
cord_uid: 9g47ga93

BACKGROUND: Vitamin D deficiency has been linked to the increased severity of numerous viral infections. OBJECTIVE: To assess whether vitamin D supplementation is safe and effective for the treatment of COVID‐19. METHODS: We searched MEDLINE, EMBASE, CENTRAL, LILACS and LOVE for randomised controlled trials (RCTs) published up to 2 March evaluating the effects of vitamin D for the treatment of coronavirus disease (COVID‐19). Two authors selected the studies and analysed the data evidence following Cochrane Recommendations. RESULTS: We included three RCTs with a total of 385 participants. We found low certainty evidence indicating that hospitalised patients under calcifediol plus standard care (SC) treatment seem to present a significantly lower risk of being admitted to ICU but no difference in mortality. We found low to very low certainty evidence that the improvement in fibrinogen levels is slightly greater in mildly symptomatic or asymptomatic patients with COVID‐19 that used cholecalciferol plus SC than in those treated with placebo plus SC (mean difference), and the patients who used cholecalciferol plus SC achieved more SARS‐CoV‐2 negativity, but not on d‐dimer, c‐reactive protein (CRP) or procalcitonin compared with the patients in the placebo plus SC group. We also found low to moderate certainty evidence that a single high dose of vitamin D does not seem to be effective for reducing mortality, length of hospital stay, ICU admissions and d‐dimer or CRP levels when used in patients with moderate to severe COVID‐19. CONCLUSIONS: As a practical implication, the use of vitamin D associated with SC seems to provide some benefit to patients with COVID‐19. However, the evidence is currently insufficient to support the routine use of vitamin D for the management of COVID‐19, as its effectiveness seems to depend on the dosage, on the baseline vitamin D levels, and on the degree of COVID‐19 severity.

Coronavirus disease shook the social, individual, economic and health systems worldwide. Since its first confirmed case in December 2019, COVID continues to spread very quickly and become fatal. As of 27 September 2020, almost 33 million cases were confirmed and over 1 million deaths occurred worldwide. 1 Never before has a virus led to a crisis that demanded so much individual and collective contribution to be overcome and with such urgency.

In response to the current coronavirus disease (COVID-19) pandemic, extraordinary efforts have been made by researchers on trying to find effective interventions. However, there is no effective treatment yet. In the meantime, the hypothesis on whether vitamin D deficiency could play a role in increasing the risk of dying from COVID-19 have arisen. [2] [3] [4] In line with this hypothesis, a recent meta-analysis using about 10 000 individual participants data from 25 randomised controlled trials (RCT), concluded that vitamin D supplementation reduced the risk of upper respiratory infections by about 19%. 5 Of note, evidence from non-randomised studies on the treatment of COVID-19 with vitamin D has recently gained traction.

Simultaneously, many physicians have held onto any thread of hope-not least because the panorama scares. However, the evidence on the effectiveness of vitamin D in patients with cannot rely on observational studies, as they are tempered by the risk of bias, especially arising from selection bias. 6 Relying on nonrandomised studies' results may lead to spurious associations and to the introduction of potentially hazardous interventions into the clinical practise mainly by the introduction of confounding factors into the comparative groups. 6 For instance, Panarese and Shanini reported that living in Northern countries-where vitamin D deficiency is more prevalent-is associated with a higher hospitalisation rate and mortality rate when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to other countries. 4 Similarly, Ilie et al have reported that mean levels of vitamin D are negatively correlated with the number of COVID-19 cases. 7

Epidemiology studies have reported that mortality and severity of COVID-19 are highly prevalent in older people, 8 in whom vitamin D deficiency is also more likely. 9 It is unknown whether other factors, such as age-related comorbidities would be the real mediators of worsening the clinical course of patients with COVID-19, or otherwise, vitamin D would actually influence outcomes of patients with COVID-19. Therefore, analysing the results of randomised controlled trials (RCTs) and the differences in using vitamin D in patients with different degrees of severity is critical for providing useful information upon which to base clinical decision-making processes.

This present article describes a rapid systematic review that followed the recommendations proposed by the Cochrane Handbook. 10 This review was performed at the Medical School of a public university in São Paulo (SP), Brazil. We performed rapid systematic review methods by not independently conducting our screening of titles and abstracts. 10 

We included RCTs of parallel design that have employed individual allocation. Cross-over design studies were also considered for inclusion. No language restrictions were applied in our eligibility criteria.

We excluded all other study designs. 

We included RCTs that evaluated vitamin D supplementation in patients with COVID-19. We prioritised hard endpoints related to deleterious consequences of COVID-19, such as respiratory derangement, inflammatory response, intensive care unit (ICU) admission, the need for invasive mechanical ventilation, among others.

Vitamin D interventions or its analogues used alone or in combination with other interventions were considered, as long as the vitamin D effect could be estimated compared with other study groups. We

• This is the first systematic review applying the principles of evidence-based medicine to find out a possible benefit of the use of vitamin D in patients with COVID-19.

• The quality of evidence was evaluated following the GRADE approach. did not restrict our criteria to any route, dosage, duration or timing of administration. 

We conducted a systematic search on the literature on 2 March 2020 in the following databases: Medline via PubMed, Embase via Elsevier, Cochrane Library-Cochrane Central Register of Controlled Trials (CENTRAL), Portal Regional BVS-LILACS and LOVE platform which comprises studies on COVID-19 from 41 databases, including preprints databases such as medRxiv and bioRxiv. We searched the RCT registry database (www.clini caltr ials.gov) to find additional published trials. Studies published in any language since November 2019 were considered for inclusion. The search strategies are shown in Data S1.

We estimated the effects of vitamin D treatments in each of the available results for our predefined outcomes. Relative risks (RR) with their 95% confidence intervals (CI) were estimated using the Review Manager 5.4.1 software.

We assessed the methodological quality of each included study using the risk of bias (RoB 2.0) table per the Cochrane Collaboration recommendations. 6 We evaluated the following domains: risk of bias arising from the randomisation process, risk of bias as a result of deviations from the intended interventions (effect of assignment to intervention), missing outcome data, risk of bias in the measurement of the outcome, risk of bias in selection of the reported result and overall risk of bias. Each study was evaluated on all six domains, assigning the classifications "low risk of bias," "some concerns of risk of bias" or "high risk of bias" to each domain.

We used the GRADE approach to classify the strength of evidence as high, moderate, low or very low. 11 We evaluated the following criteria: risk of bias, inconsistency, imprecision and indirectness. We created the summary of findings table considering the primary outcomes from comparisons using the GRADEpro platform.

Our database search strategies yield 578 records. After the twostage screening process, we excluded duplicated reports and that were clearly irrelevant or not directly related to the review question.

We assessed 31 full-text studies for further scrutiny. Three of them fulfilled our eligibility criteria. The PRISMA flow diagram is shown in Figure 1 .

We included three parallel, randomised, double-masked pilot clinical trials ( Table 1) . As the studies included very different degrees of COVID-19 severity and pharmacological characteristics (combination with other treatments, dosage and schedules), pooling their results together was not possible. One study 12 evaluated the effect of calcifediol treatment on ICU admission and mortality rate among Spanish patients hospitalised for COVID-19. All hospitalised patients received standard care (as per hospital protocol), including a combination of hydroxychloroquine (400 mg every 12 hours on the first day, and 200 mg every 12 hours for the following 5 days), azithromycin (500 mg orally for 5 days) and for patients with pneumonia and NEWS score ≥5, ceftriaxone 2 g intravenously every 24 hours for 5 days was added to hydroxychloroquine and azithromycin. The 

We excluded 28 studies 15-42 as they were ongoing studies, with no results available.

There was some concern for the overall risk of bias in the Entreans-Castillo 2020 study 12 as it is not clearly described how the randomisation process was concealed and how interventionists were blind to the allocation of the interventions. The overall risk of bias in the Rastogi et al's study 13 was judged as high as the placebo used in the study was not exactly matched with regards to the taste and consistency with the cholecalciferol nano-formulation and possible bias arising from the randomisation process and from the blinding of outcome assessors. Murai et al 14 was the only study judged as having an overall low risk of bias. The risk of each study is presented in Figure 2 .

We rated the certainty of evidence using the GRADE approach. 11 We found low certainty of evidence for all the reported outcomes. We downgraded one level resulting from methodological limitation and one level resulting from the imprecision of the estimated effects, except for D-dimer, which we downgraded one level resulting from methodological limitation and two levels resulting from the imprecision of the estimated effects.

To provide graphical visualisation of the results and to calculate mean differences between groups and risk ratios, we estimated the mean and SD of all outcomes by using median and interquartile ranges from primary studies as recommended by Wan et al 43 and Cochrane Handbook.

We were not able to find any difference in mortality between using calcifediol plus standard care in patients with COVID-19 compared 

Patients with COVID-19 that used calcifediol plus standard care presented a significantly lower risk of being admitted to ICU compared with those receiving standard care alone [RR 0.04; 95% CI 0.01 to 0.29]-low certainty of evidence ( Figure 5) . We were not able to find any difference on ICU admission between using vitamin D compared with placebo [RR 0.75; 95% CI 0.44 to 1.29]-moderate certainty of evidence ( Figure 6 ). 

No difference was found between using vitamin D compared with using placebo on the duration of invasive mechanical ventilation.

We were not able to find any difference between using vitamin D compared with placebo on the length of hospital stay (MD −1.30; 95% CI −2.63 to 0.03)-low certainty of evidence (Figure 7 ).

We were not able to find any difference in D-dimer levels be- 

This is the first systematic review applying the principles of evidence-based medicine to find out a possible benefit of the use of vitamin D in patients with COVID-19. We found low certainty of evidence from one RCT demonstrating that the use of calcifediol in Therefore, the trial could have had inadequate power to exclude small, but clinically meaningful differences between the groups. Of interest, the percentage of patients with vitamin D deficiency included in this trial was relatively low, which seems to be important clinical information to be further analysed.

These questions may be answered by the 28 ongoing studies evaluating the effects of vitamin D in patients with COVID-19

found through our comprehensive search strategies. We believe that these RCTs will provide high-quality evidence and a representative sample from which more precise effects will be estimated.

Furthermore, these studies may be able to provide reliable evidence upon which to base clinical decision-making processes, covering the gaps on the effects of vitamin D used alone or combined to other treatments, best dosage, the timing of usage and characteristics of patients who are more likely to benefit from vitamin D treatment.

As a practical implication, the use of vitamin D in association with standard care seems to provide some benefit to patients with COVID-19. However, the evidence is currently insufficient to support the routine use of vitamin D for the management of COVID-19, as its effectiveness seems to depend on the dosage, on the baseline vitamin D levels, and on the degree of severity of the disease. So far, the safety of vitamin D in patients with SARS-CoV-2 infection is still considered uncertain and no conclusions can be drawn. The results of the ongoing high-quality RCTs are necessary to provide more precise and reliable information on the proper use of vitamin D in patients with COVID-19 and to guide clinical decision-making processes.

None. 

The authors confirm that the data supporting the findings of this study are available within the article or its supplementary material.

Aline Pereira da Rocha https://orcid.org/0000-0002-0863-6500

Ana Carolina Pereira Nunes Pinto https://orcid.org/0000-0002-1505-877X

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Additional Supporting Information may be found online in the Supporting Information section

Insufficient evidence for vitamin D use in COVID-19: A rapid systematic review