Next Article in Journal
Premature Birth is an Independent Risk Factor for Early Adiposity Rebound: Longitudinal Analysis of BMI Data from Birth to 7 Years
Previous Article in Journal
Vitamin E Levels in Ethnic Communities in Malaysia and Its Relation to Glucose Tolerance, Insulin Resistance and Advanced Glycation End Products: A Cross-Sectional Study
Reply

Reply to: “Vitamin D Insufficiency May Account for Almost Nine of Ten COVID-19 Deaths: Time to Act. Comment on: Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients 2020, 12, 2757”

1
Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany
2
Department of Internal Medicine IV, University of Heidelberg, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(12), 3643; https://doi.org/10.3390/nu12123643
Received: 28 October 2020 / Accepted: 5 November 2020 / Published: 27 November 2020
(This article belongs to the Section Micronutrients and Human Health)
We thank Brenner and Schöttker for their comment [1] and interest in our recent publication [2] and for providing us with the opportunity to extend the discussion regarding our observations and the potential role of vitamin D (VitD) supplementation in reducing disease severity and the risk of mortality in individuals infected with SARS-CoV-2.
As already pointed out and discussed [2], the results of observational studies always need to be interpreted with caution, since they are vulnerable to bias and unknown confounders. Although a covariate-adjusted hazard of death of ~11 for VitD insufficient patients (25(OH)D <20 ng/mL at baseline) was observed, it should be noted that due to the small sample-size and particularly the low number of death events, we were only able to include a limited number of confounding variables (age, gender, and presence of any comorbidity) in our models. However, as already pointed out [2], the presence of additional confounding risk factors for COVID-19 severity, such as obesity or specific comorbidities, as well as other unrecognized factors, should also be borne in mind, in particular since many of these at-risk patients are also disproportionally affected by poor VitD status. In other words, in an observational study design, it cannot be excluded that VitD deficiency represents a surrogate marker for a general micronutrient deficiency, which in turn reflects only the patient’s overall health status. For instance, obesity, which is associated with chronic low-grade inflammation and higher IL-6 levels and risk of hospitalization from respiratory tract infections, was recently also shown to be a determinant of COVID-19 severity and mortality [3,4,5]. In addition, although evidence is accumulating that suggests COVID-19 mortality to be associated with poor VitD status [6,7,8], studies which found no association with disease outcomes [9] or mortality [10] also need to be acknowledged. Therefore, in the absence of a randomized controlled trial on VitD treatment, no causal association between VitD status and severity/outcome of COVID-19 can be inferred. On the other hand, as rightly pointed out by Brenner and Schöttker [1], results of such trials, particularly the large VIVID trial [11], will not be available in the near future.
In general, as in all treatment decisions, the potential benefits of therapy must outweigh the risks. We agree with Brenner and Schöttker that in the case of VitD, the risk–benefit ratio is probably skewed far in favor of benefits. Therefore, pending randomized controlled trial evidence, and facing an emerging second wave of SARS-CoV-2 infections, it would seem uncontroversial to promote efforts to achieve sufficient 25(OH)D levels, particularly for high-risk groups where VitD deficiency is highly prevalent, and advocate for targeted VitD supplementation for all SARS-CoV-2 infected individuals.

Author Contributions

A.R. and U.M. wrote the reply. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Brenner, H.; Schöttker, B. Vitamin D Insufficiency May Account for Almost Nine of Ten COVID-19 Deaths: Time to Act. Comment on: Vitamin D deficiency and outcome of COVID-19 patients. Nutrients 2020, 12, 2757. Nutrients 2020, 12, 3642. [Google Scholar] [CrossRef]
  2. Radujkovic, A.; Hippchen, T.; Tiwari-Heckler, S.; Dreher, S.; Boxberger, M.; Merle, U. Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients 2020, 12, 2757. [Google Scholar] [CrossRef] [PubMed]
  3. Chiappetta, S.; Sharma, A.M.; Bottino, V.; Stier, C. COVID-19 and the role of chronic inflammation in patients with obesity. Int. J. Obes. 2020, 44, 1790–1792. [Google Scholar] [CrossRef] [PubMed]
  4. Anderson, M.R.; Geleris, J.; Anderson, D.R.; Zucker, J.; Nobel, Y.R.; Freedberg, D.; Small-Saunders, J.; Rajagopalan, K.N.; Greendyk, R.; Chae, S.R.; et al. Body Mass Index and Risk for Intubation or Death in SARS-CoV-2 Infection: A Retrospective Cohort Study. Ann. Intern. Med. 2020, M20-3214. [Google Scholar] [CrossRef]
  5. Hamer, M.; Gale, C.R.; Kivimäki, M.; Batty, G.D. Overweight, obesity, and risk of hospitalization for COVID-19: A community-based cohort study of adults in the United Kingdom. Proc. Natl. Acad. Sci. USA 2020, 117, 21011–21013. [Google Scholar] [CrossRef] [PubMed]
  6. Carpagnano, G.E.; Di Lecce, V.; Quaranta, V.N.; Zito, A.; Buonamico, E.; Capozza, E.; Palumbo, A.; Di Gioia, G.; Valerio, V.N.; Resta, O. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J. Endocrinol. Investig. 2020, 1–7. [Google Scholar] [CrossRef]
  7. Entrenas Castillo, M.; Entrenas Costa, L.M.; Vaquero Barrios, J.M.; Alcalá Díaz, J.F.; López Miranda, J.; Bouillon, R.; Quesada Gomez, J.M. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J. Steroid Biochem. Mol. Biol. 2020, 203, 105751. [Google Scholar] [CrossRef] [PubMed]
  8. Maghbooli, Z.; Sahraian, M.A.; Ebrahimi, M.; Pazoki, M.; Kafan, S.; Tabriz, H.M.; Hadadi, A.; Montazeri, M.; Nasiri, M.; Shirvani, A.; et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS ONE 2020, 15, e0239799. [Google Scholar] [CrossRef]
  9. Pizzini, A.; Aichner, M.; Sahanic, S.; Böhm, A.; Egger, A.; Hoermann, G.; Kurz, K.; Widmann, G.; Bellmann-Weiler, R.; Weiss, G.; et al. Impact of Vitamin D Deficiency on COVID-19-A Prospective Analysis from the CovILD Registry. Nutrients 2020, 12, 2775. [Google Scholar] [CrossRef] [PubMed]
  10. Baktash, V.; Hosack, T.; Patel, N.; Shah, S.; Kandiah, P.; Van Den Abbeele, K.; Mandal, A.K.J.; Missouris, C.G. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad. Med. J. 2020. [Google Scholar] [CrossRef]
  11. Wang, R.; DeGruttola, V.; Lei, Q.; Mayer, K.H.; Redline, S.; Hazra, A.; Mora, S.; Willett, W.C.; Ganmaa, D.; Manson, J.E. The vitamin D for COVID-19 (VIVID) trial: A pragmatic cluster-randomized design. Contemp Clin. Trials. 2020, 106176. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop