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4 COVID-19 AND VITAMIN D: DATA FROM STUDIES

Some authors propose that VitD status could also strongly account for variability in COVID-19 severity.31 This suggestion might be supported by the data from European countries: there exists a negative correlation between levels of mean 25OH-D and number of cases of COVID-19 for 1 million (1 M) of population in each country, as well as a negative correlation between levels of mean 25OH-D and the number of deaths caused by COVID-19/1 M.23 Similar findings regarding mean 25OH-D levels and COVID-19 mortality rates were found by others in the study on data from 12 European countries.17 However, a retrospective study on data from 20 European countries showed a significant negative correlation for levels of mean vitamin D with COVID-19 cases, but not with death rates per 1 M of population.32 But in a recent meta-analysis with a total of 1,368 COVID-19-positive patients, low VitD levels (ie deficiency) were significantly associated with poorer patient outcomes (eg development of ARDS, intensive care unit admission or death) and prognosis.33
Taken together, all these facts undoubtedly suggest relationships between low VitD and COVID-19. Some authors even suggested that patients having VitD deficiency should be considered as high risk group for getting severe illness from COVID-19.37 In addition, more and more humans haverisk of being less exposed to sunlight because of ‘stay at home’ mitigation strategies,3, 17 consequently, many of us could be named as members of risk group for VitD deficiency, and, paradoxically, could be at a higher risk of being ill with COVID-19 or other infections. Certainly, further observational studies are needed; some guidelines for research in this field have also been recently suggested.31, 37

5.3 Modulation of specific immunity and inflammation, and can weakening of the ‘cytokine storm’
VitD suppresses responses mediated by the T helper cell type 1 (Th1), by primarily repressing production of inflammatory cytokines IL-2 and interferon gamma (INFγ); also, promotes cytokine production by the T helper type 2 (Th2) cells, which helps enhance the indirect suppression of Th1 cells by complementing this with actions mediated by a multitude of cell types; and also promotes induction of the T regulatory cells, thereby inhibiting inflammatory processes.4 Cytokine storm (CS) can be triggered by infectious diseases, rheumatic diseases and tumour immunotherapy, and it generally presents as systemic inflammation and multiple organ failure.5 It is well known that CS is one of the main mechanisms that can severely damage the lungs and other organs in patients suffering from severe COVID-19. CS is characterised by uncontrolled release of various pro-inflammatory cytokines and chemokines, eg interleukin (IL)-1 beta, IL-6, IL-1RA, TNF (tumour necrosis factor)-alpha, IL-17, monocytes chemoattractant protein-1, and many others, followed by increased serum ferritin levels, decreased natural killer (NK) cell count and alleviated NK function. All this results in damage of healthy cells, vascular leakage, severe exfoliation of alveolar epithelial cells, alveolar septal widening and damage, oedema and inflammatory cell infiltration, ultimately leading to lung dysfunction and hypoxia, as well as to hypercoagulability, thrombosis and multiple organ damage.2, 3, 38 VitD is thought to be beneficial for prevention and/or treatment of CS, via the ability to decrease synthesis and secretion of various pro-inflammatory cytokines and to increase synthesis of some anti-inflammatory cytokines.4, 5, 13, 19, 38

6 IMPROVING VITAMIN D STATUS: VARIABILITY IN RECOMMENDATIONS

VitD supplementation should be considered an adjuvant therapy for COVID-19 patients and also whole population supplementation might be recommended. Improvement in circulating 25OH-D levels opens possibilities for slowing disease progression or even improving survival of patients, and keeping in mind the good tolerability and safety of even high doses of vitamin D (for almost all patients), this approach complies primum non nocere principle.37, 47 Indeed, it was postulated that, in general, the risk of overdosing VitD tends to be next to zero, unless very large doses without physician supervision are being used for an extended period of time or mega-doses such as 1 million IU daily are taken for a few days.19, 57 It was also speculated that VitD could be a cheaper alternative for expensive drugs suggested for treatment of COVID-19 patients, eg tocilizumab,31 or might have potency to be used together with drugs approved for COVID-19 treatment, eg remdesivir.58 It is reasonable to advocate for VitD supplementation more widely during COVID-19 pandemic, as supplementing VitD in people who are already ill might be too late to be effective—in particular, in those patients who are presented to hospital in the hyperinflammatory stage of the disease.59, 60

7 VITAMIN D DOSING: CREATING PRACTICE GUIDELINES

In developing practical guidelines for VitD supplementation in adults during the COVID-19 pandemic, several main aspects should be considered:
Daily VitD dose up to 10 000 IU is considered generally safe for almost all patients.4 Only few patients are ‘vitamin D hypersensitive’, since they have or are at higher risk of develop hypercalcaemia even from small supplemental VitD doses, eg in case of primary hyperparathyroidism or granulomatous diseases such as sarcoidosis or active tuberculosis,26, 63, 75 or in rare cases when catabolism of VitD metabolites is impaired because of mutation of specific genes (eg CYP24A1).76
If recent 25OH-D measurement is not available, all those without prior supplementation could be considered as potential VitD-deficient patients who might require high VitD doses to reach sufficient 25OH-D levels. Some patients, eg obese persons, the elderly or patients having malabsorption syndrome (further in the text named VitD risk groups) might require much higher VitD doses.26, 59, 63
If recent 25OH-D measurement is not available, those already taking supplements should increase their doses 1.5-2-fold, since the older target for their 25OH-D level is supposed to be at least 30 ng/mL, and not at least 40 ng/mL as it is suggested currently. If the recommended doses from previous guidelines 26, 63 are multiplied by 2, they will be closer to or within the recommended range of 5000-10 000 IU/d as discussed above.
If a patient is on supplementation and the VitD supplement is well tolerated, consider using the same supplement.
Regarding dosing regime, taking supplements daily or once a week seems to be a better choice than taking mega-doses once in 1-3 months.4, 19, 35
If currently 25OH-D measurement is not available and a large dose (either daily or weekly) is still prescribed, analysis of 25OH-D levels (preferably, serum calcium levels, too) should be performed in no longer than 1-1.5 month, for two reasons: (a) to evaluate the efficacy of supplementation (very important in case malabsorption is suspected), and (b) to detect VitD intoxication early enough.26, 32, 63, 77
In summary, based on these assumptions, brief simplified recommendations may be drafted:
All inpatients suffering from COVID-19 should be tested for 25OH-D levels at the admission day. If 25OH-D levels are below 40 ng/mL, VitD dosing according to ‘Grant’s schema’ or ‘Ebadi’s schema’ should be started as soon as possible.
Outpatients with COVID-19 and those without COVID-19:
If baseline 25OH-D levels are unknown (measurement is not possible at the moment):
◦ For those already on supplementation, increase the doses twofold (however, daily doses should be within range 4000-10 000 IU) for 1-1.5 month; then check 25OH-D levels;
◦ For those without prior supplementation, suggest VitD dose 4000 IU/d (for those of VitD risk groups—consider 6000-8000 IU/d), or alternatively, 50 000 IU once a week; check 25OH-D levels in a 1-1.5 month.
If current 25OH-D levels were measured, strategy depends on the results:
◦ Levels less than 40 ng/mL: if on supplementation, increase doses twofold (daily doses should be within range 4000-10 000 IU) for 1-1.5 month, then check 25OH-D levels; if without prior supplementation—suggest VitD dose 4000 IU/d (for those of VitD risk groups—consider 6000-8000 IU/d), or alternatively, 50 000 IU once a week; check 25OH-D levels in 1-1.5 month.
◦ Levels 40-60 ng/mL: follow the current supplement dosing.
Levels >60-100 ng/mL: suspend VitD supplementation for 1 or 2 months, then check 25OH-D levels.
Levels >100 ng/mL: stop VitD supplementation, access calcaemia and calciuria, administer treatment in case of hypercalcaemia etc as described elsewhere.26

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