Preventing a covid-19 pandemic

Dear Editor,
We have read with interest the Editorial recently published in BMJ by Watkins and related rapid responses by Cobbold, Garami, Maestri and Rhein. In most of these comments a possible helpful role of vitamin D in the prevention or the response to Covid19 pandemic has been proposed or discussed-. In particular, vitamin D deficiency has been reported to increase predisposition to systemic infections and impaired immune response or even autoimmune diseases (1). Moreover, an interesting metaanalysis has shown that vitamin D supplementation can prevent respiratory infections (2)
Italy is the Country that is paying the highest death toll to Covid19 infection in the whole world (reaching today the impressive number of 4000 in less than four weeks and exceeding already by far the number of deaths of slightly more than 3.200 so far reported in China) ) (3).
From the analysis of epidemiological data available particularly in the Chinese Literature but also in the reports of the Italian Ministry of Health the majority of deaths is concentrated in the elderly with common, although not necessarily deadly per se , comorbidities such as hypertension, diabetes or obesity(4). In fact, it has been suggested that the elevated mean age of the Italian population (5) could be a predisposing factor to the severity and elevated mortality related to Covid infection. This has led to the hypothesis that Italians may die with Coronavirus infection rather than for Coronavirus infection,
Nevertheless, a convincing explanation on the reason(s) of this so far anomalous and deadly impact of Covid in Italy and particularly in the Northern Regions has not so far been provided.
Interestingly, epidemiological data report that Italy is one of the Countries with the highest prevalence of hypovitaminosis D in Europe. A study from Isaia et al on 700 women aged 60-80 yrs in Italy found values of 25OH vitaminD lower than 5 ng/ml in 27% of the women and lower than 12 ng/ml in as many as 76%. (6) Moreover, the same group found a very high prevalence of hypovitaminosis D in elderly women with diabetes (7). Finally, another Italian study found a winter prevalence of hypovitaminosis D up to 32% of healthy postmenopausal women and to 82% in patients engaged in long-term rehabilitation programmes because of various neurological disorders.(8). Obesity has also been suggested to be linked to low vitamin D and higher vitamin D requirements (9)
Vitamin D status largely depends on sun exposure since at odds with all other vitamins (in fact it is a steroid hormone) the amount introduced with diet is far from being sufficient (1). The huge amount of the population with low circulating vitamin D levels in Italy is due to the historical lack of a program of food fortification with vitamin D ( at odds with what has been done since several decades in many European countries leading to what is known as the Scandinavian paradox, i.e. the highest level of vitamin D in northern european Countries at low sunshine exposure vs the Southern Countries at higher sunshine exposure) as well as the change in lifestyle with more sedentary type of working and living plus the different climate conditions in the Northern vs Southern regions of the Country (10).
Therefore, based on the previous considerations it could be hypothesized that low vitamin D could be the link between age, comorbidities and increased susceptibility to complications and mortality due to Covid19 infection in the northern regions in Italy.
Two other further general considerations may contribute to the argument of contribution of low vitamin D to the impact of Covid19: a) in severely compromised patients: patients with acute illness, whether they are in the intensive care unit or not, have very low levels of 25(OH)vitaminD (11) Moreover, some authors think that poor vitamin D status may aggravate the health outcome of ICU patients and correction with (high doses) of vitamin D of poor vitamin D status could decrease morbidity and mortality (12); b) in general population: home confinement is the most used preventive measure against the spreading of Covid19 infection in many Countries and in Italy in particular. Total absence of sunlight exposure may cause in large part also of the younger population a decrease or worsening in the vitamin D status. (13)
In order to corroborate our hypothesis it should be necessary to look at 25OH vitamin D levels in hospitalized patients with Covid19 infection and in different stages of the disease. However, even in absence of a proof of our concept, in an era of restrictive mesures of Health authorities concerning the reimbursability of vitamin D (14) we think reasonable a message reinforcing the importance of maintaining vitamin D treatment in those already diagnosed with hypovitaminosis D and considering the supplementation with vitamin D of elderly comorbid persons at home confinement (15). Issue of universal supplementation with vitamin D due to high risk of complicated Covid19 infection in Italy or in other Countries including the hospitalized, in and not in ICU, patients remains open.

REFERENCES
1. Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019 Aug 1;40(4):1109-1151.
2. Martineau AR,Jolliffe DA, Hooper RL et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583
3. covid19@gimbe.org March 20 2020
4. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. Published online February 07, 2020. doi:10.1001/jama.2020.1585
5. www.istat.org February 11 2020
6. Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D, Adami S. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors Osteoporos Int. 2003 Jul;14(7):577-82
7. Isaia G, Giorgino R, Adami S. High prevalence of hypovitaminosis D in female type 2 diabetic population
Diabetes Care. 2001 Aug;24(8):1496
8. Romagnoli E, Caravella P, Scarnecchia L, Martinez P, Minisola S. Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients.Br J Nutr. 1999 Feb;81(2):133-7.
9. Formenti AM, Tecilazich F, Frara S, Giubbini R, De Luca H, Giustina A. Body mass index predicts resistance to active vitamin D in patients with hypoparathyroidism Endocrine. 2019 Dec;66(3):699-700
10. Giustina A, Adler RA, Binkley N, et al. Controversies in Vitamin D: Summary Statement From an International Conference. J Clin Endocrinol Metab. 2019 Feb 1;104(2):234-240.
11. . Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care 2012;15(2):188–193.
12. Christopher KB. Vitamin D and critical illness outcomes. Curr Opin Crit Care 2016;22(4):332–338.
13. Nota 96. Gazzetta Ufficiale Serie Generale n. 252 del 26/10/2019.
14. Giustina A, Adler RA, Binkley N, et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Rev Endocrinol Metab Dis 2020 ] Mar 17. doi: 10.1007/s11154-019-09532-w. [Epub ahead of print]
15. Ebeling PR, Adler RA, Jones G, et al. MANAGEMENT OF ENDOCRINE DISEASE: Therapeutics of Vitamin D. Eur J Endocrinol. 2018 Oct 12;179(5):R239-R259

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