This retrospective observational single center study reports data about the possible association between vitamin D serum level and disease severity and prognosis in patients affected by SARS-CoV-2 with acute respiratory failure.
Since March 2020, the Policlinic of Bari in Italy was transformed in a COVID-19 Hospital. In our RICU, patients referred to Emergency Department with acute respiratory failure due to COVID-19 but without need of intubation and invasive ventilation in ICU were admitted. Our study population was characterized by a mortality risk assessed by SOFA score greater than 36% , with high levels of inflammation indices and impaired respiratory exchanges, up to ARDS. In particular, 88% of our patients had mild to severe ARDS, showing a PaO2/FiO2 ratio between 300 and 200 in 38%, between 100 and 200 in 38%, and < 100 in 14% of patients.
In these patients, we found high prevalence of hypovitaminosis D (81%). Twenty-four percent of patients had severe deficiency, showing vitamin D serum level below than 10 ng/mL. In the position statement of the European Calcified Tissue Society, it is reported that vitamin D deficiency is common in Europe, especially in Western, Southern and Eastern Europe (30–60%) and in Middle East countries (> 80%), and that severe deficiency is found in > 10% of Europeans. In addition to sun exposure and dietary intake, age over 70 years and institutionalization are presented as the main risk factors for impaired vitamin D status . Our study was conducted during the quarantine period, in the winter months, in patients with an average age over 65 years, some of whom were institutionalized; all these factors could explain our results.
Based on vitamin D serum levels we divided our cohort into four groups: 19% of patients had no hypovitaminosis D, 26% had insufficiency, 31% had moderate deficiency, and 24% had severe deficiency. No statistically significant differences were found between the groups regarding inflammation indexes and respiratory exchanges data. IL-6 levels are higher in patients with severe vitamin D deficiency but this data do not reach statistical significance. This might be related to the sample size, therefore analysis on a larger number of patients would be needed. By contrast, a survival analysis showed that, after 10 days of hospitalization, patients with severe vitamin D deficiency had a significantly higher mortality risk than the others. This finding may suggest a possible role for the vitamin D supplementation in the supportive treatment of COVID-19 patients.
These data are in line with results of a study conducted by Ilie et al. They focused on mean vitamin D levels in European countries (severely low in aging population especially in Italy, Spain and Switzerland) and observed a negative correlation between vitamin D levels and COVID-19 cases and mortality in the population of those countries . Accordingly, in a recent study, Grant et al. reported that vitamin D could reduce the risk of influenza and COVID-19. The outbreak occurred in winter, a time when vitamin D concentrations are lowest; on the other hand, the number of cases in the Southern Hemisphere near the end of summer are low. Vitamin D deficiency has been found to contribute to ADRS; case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration.
Altogether, these considerations support the recommendation that people at risk of influenza and/or COVID-19 consider vitamin D supplementation to raise their 25(OH)D concentrations above 40–60 ng/mL, and that treatment of patients infected with influenza and/or COVID-19 includes higher vitamin D doses. However, randomized controlled trials and large population studies should be conducted to evaluate these recommendations specifically in COVID-19 patients .
Furthermore, in a recent review, Panfili and colleagues report some evidence of a role of vitamin D in preventing lung fibrosis, described as a common complication of ARDS and that could be a long-term issue in these patients. This antifibrotic role could be an additional element supporting the use of vitamin D supplementation before and after COVID 19 infection. However, this hypothesis will be supported by studies with longer follow-up on survivors .
The association between hypovitaminosis D, airways inflammation and increased risk of respiratory infections started before the COVID-19 era when a large body of studies evaluated the efficacy of vitamin D supplementation as adjunctive treatment in patients with respiratory diseases. Lehouck et al. explored the role of supplementation with high doses of vitamin D in reducing the incidence of COPD exacerbations. In that study, patients with moderate to very severe COPD and a history of recent exacerbations were randomized to receive 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year. No differences in terms of median time to first exacerbation, exacerbation rate, FEV1, hospitalization, quality of life and death were found between the vitamin D and placebo groups. However, a post hoc analysis conducted on patients with severe vitamin D deficiency (< 10 ng/mL) showed a significant reduction in exacerbation rate in vitamin D group .
Moreover, a meta-analysis conducted by Martineau et al. on 25 RCTs highlighted that vitamin D supplementation reduced the risk of acute respiratory infections, and that the protective vitamin D effects were more evident in those individuals with 25(OH)D baseline concentrations below 25 nmol/L at baseline . In our study, a higher mortality risk was related to lower 25(OH)D levels.
In addition, along with age and levels of troponin, creatinine and IL-6, severe vitamin D deficiency emerged as an independent survival factor in COVID-19 patients. This suggest that vitamin D supplementation may not protect against COVID-19 infections, but, in case of infection, may reduce the severity of the disease and consequently the risk of death.
In our RICU, no correlation between inflammations indices, respiratory exchanges data and vitamin D serum level was found. This might be related with the severe clinical conditions of these patients, characterized by moderate to severe hypoxemic respiratory failure, requiring treatment with non-invasive mechanical ventilation or high-flow oxygen. Moreover, in our population the large majority was already characterized by hypovitaminosis D. Nevertheless, the lack of correlation between inflammatory indices and vitamin D levels may be related to sample size but it may also suggest that severe vitamin D deficiency may influence outcomes independently of its immunomodulatory properties.
This study presented some limitations. Firstly, the sample size that is modest. As previously mentioned, this may have limited the results of statistical analyzes, especially those conducted within the cited four subgroups. The classification in four groups was used according to clinical practice, in which different levels of hypovitaminosis D provide for different therapeutic dosages. Secondly, the relatively short follow-up of patients enrolled, related to hospitalization times in a RICU. Indeed, patients admitted to our RICU for acute respiratory failure due to COVID-19, were transferred to a lower-intensity care wards, in case of stabilization of clinical conditions, or to ICU, in case of worsening respiratory failure. This aspect, associated with the severity of the clinical conditions of some patients, reduced hospitalization times and consequently patients follow-up.
In conclusion, the results of our study show a high prevalence of hypovitaminosis D in COVID-19 patients treated in a RICU. Higher risk of mortality was found in patients with severe vitamin D deficiency. Further studies need to be conducted on a larger population, to demonstrate whether adjunctive treatment with vitamin D might be effective in improving disease outcomes and in reducing mortality risk.