between truth and wishful thinking
Pasquale Strazzullo, Domenico Rendina and Paola Iaccarino Idelson
Viral infections and immunity
Viral infections in general, e.g. influenza and, as we have recently seen, Coronavirus infections, affect people of all ages, but their complications, especially the most severe ones, are more frequent in elderly people. This is partly due to the phenomenon of "immunosenescence", a weakening of the immune function linked to ageing. The latter is due in turn to the presence of antigenic problems and chronic inflammation, some of which are also influenced (in a positive or negative way) by our eating habits, or by conclamated nutritional deficiencies. Among the latter, there is no doubt that one of the most important and most frequent deficiency is that of vitamin D, which can be defined as endemic in the population over 65 years of age and especially high among the guests of nursing homes, frequent victims, as we have seen, of the current pandemic. Vitamin D deficiency is more frequent, though not at all exclusive, in the elderly, both because of the lower level of endogenous vitamin synthesis (due to reduced exposure to the sun's rays and lower biosynthetic capacity secondary to skin hypotrophy) and because of a poor intake through food.
Vitamin D, immune response and inflammation
But why is vitamin D deficiency linked to the immune response and thus to the susceptibility to infections and to the infection resistance itself? Many studies, more or less recent, have shown that the cells of the immune system own the vitamin D receptor and also the enzymatic mechanisms to convert the vitamin into its active form, calcitriol. This fact suggests that the vitamin or its active form plays a role in establishing immunity. In agreement with this hypothesis, other studies have suggested that vitamin D actually exerts immunomodulatory actions and is able to modulate the inflammatory response to bacterial and viral agents. In the course of the current pandemic, it has been shown that the ability of the affected organism to react to the infection through an adequate immune response and to express an appropriate level of inflammatory response that does not itself become harmful to the patient are equally important.
Recent studies, also Italian ones, such as the “InCHIANTI”, have shown that elderly subjects with low levels of vitamin D often have higher inflammatory response values, as indicated by higher levels of plasma cytokines such as C reactive protein and some interleukins, a phenomenon observed particularly during the winter months when vitamin D reserves tend to decrease further. A recent systematic review of studies conducted on cell lines of the immune system has shown an anti-inflammatory action of vitamin D mediated by a lower production of some cytokines and a reduced intensity of different molecular expressions of inflammation. Other experimental studies have suggested the possibility that vitamin D exerts antimicrobial activities through the production of specific peptides, such as catelicidin (LL-37), an antimicrobial factor produced by phagocytic cells, which provides particular protection against bacterial infections, e.g. tuberculosis and other respiratory infections. The expression of this peptide in the respiratory epithelium appears to be increased by active metabolites of vitamin D. Catelicidin may also have an antiviral action against influenza. Finally, to vitamin D has been attributed the ability to influence the production of reactive oxygen species (ROS), which in turn are implicated in the mechanisms of inflammation.
Not surprisingly, many studies have investigated the vitamin D ability of affecting the response to vaccines, primarily influenza. This is also very relevant to the current pandemic. In fact, the long-term public health strategy focuses on the availability of a vaccine against COVID-19 infection that can, like the flu vaccine, reduce the risk of serious and life-threatening complications of the infection, particularly for older people. However, we know that the effectiveness of vaccines is often lower for older people than for younger people because of what has been said above and perhaps also because of the more frequent vitamin D deficiency.
What are the real perspectives for the correction of vitamin D deficiency?
In contrast to the results of the experimental studies, which are very promising regarding a possible protective role of vitamin D, the results of clinical trials are unfortunately much less encouraging.
There are still few reliable clinical trials, i.e. the so-called controlled and randomised intervention trials, some of which have produced controversial preliminary results. In fact, in some cases, these studies have not been conducted in a way that provide comprehensive reliable answers. In particular, intervention trials in humans have not provided conclusive or particularly promising answers with regard to: the prevention of general respiratory infections, the outcome of patients with respiratory infections, and to the possible better outcome of influenza vaccination. Consequently, at the current state of knowledge, there is no evidence that the correction of a vitamin D deficiency is useful to strengthen the immune system and to prevent or attenuate the course of infections in general and respiratory infections in particular.
However, this conclusion does not eliminate the fact that a widespread vitamin D deficiency exists and is particularly acute in the elderly population, especially if their mobility is reduced or null, as for guests of nursing homes. Plasma dosage of 25(OH) vitamin D is absolutely necessary in this population group in order to document the nutritional condition and to correct the deficiency according to current protocols. A relatively rapid correction requires the administration of high doses of vitamin D for a few weeks with precise remote control and always on prescription. A daily supplement may, however, be useful once the deficiency has been corrected to maintain the values achieved in view of the high frequency of recurrence and the modest contribution of vitamin D present only in some foods.
The correction of vitamin D deficiency has as its main objective the maintenance of bone health and good skeletal muscle function, which is also essential for the prevention of falls and the consequent complications that actually reduce life quality and expectancy of the patient. Whether the correction of vitamin D deficiency can also reduce the risk of metabolic and vascular diseases and support the immune system is still part of wishful thinking.
But why is vitamin D deficiency linked to the immune response and thus to the susceptibility to infections and to the infection resistance itself? Many studies, more or less recent, have shown that the cells of the immune system own the vitamin D receptor and also the enzymatic mechanisms to convert the vitamin into its active form, calcitriol. This fact suggests that the vitamin or its active form plays a role in establishing immunity. In agreement with this hypothesis, other studies have suggested that vitamin D actually exerts immunomodulatory actions and is able to modulate the inflammatory response to bacterial and viral agents. In the course of the current pandemic, it has been shown that the ability of the affected organism to react to the infection through an adequate immune response and to express an appropriate level of inflammatory response that does not itself become harmful to the patient are equally important.
Recent studies, also Italian ones, such as the “InCHIANTI”, have shown that elderly subjects with low levels of vitamin D often have higher inflammatory response values, as indicated by higher levels of plasma cytokines such as C reactive protein and some interleukins, a phenomenon observed particularly during the winter months when vitamin D reserves tend to decrease further. A recent systematic review of studies conducted on cell lines of the immune system has shown an anti-inflammatory action of vitamin D mediated by a lower production of some cytokines and a reduced intensity of different molecular expressions of inflammation. Other experimental studies have suggested the possibility that vitamin D exerts antimicrobial activities through the production of specific peptides, such as catelicidin (LL-37), an antimicrobial factor produced by phagocytic cells, which provides particular protection against bacterial infections, e.g. tuberculosis and other respiratory infections. The expression of this peptide in the respiratory epithelium appears to be increased by active metabolites of vitamin D. Catelicidin may also have an antiviral action against influenza. Finally, to vitamin D has been attributed the ability to influence the production of reactive oxygen species (ROS), which in turn are implicated in the mechanisms of inflammation.
Not surprisingly, many studies have investigated the vitamin D ability of affecting the response to vaccines, primarily influenza. This is also very relevant to the current pandemic. In fact, the long-term public health strategy focuses on the availability of a vaccine against COVID-19 infection that can, like the flu vaccine, reduce the risk of serious and life-threatening complications of the infection, particularly for older people. However, we know that the effectiveness of vaccines is often lower for older people than for younger people because of what has been said above and perhaps also because of the more frequent vitamin D deficiency.
What are the real perspectives for the correction of vitamin D deficiency?
In contrast to the results of the experimental studies, which are very promising regarding a possible protective role of vitamin D, the results of clinical trials are unfortunately much less encouraging.
There are still few reliable clinical trials, i.e. the so-called controlled and randomised intervention trials, some of which have produced controversial preliminary results. In fact, in some cases, these studies have not been conducted in a way that provide comprehensive reliable answers. In particular, intervention trials in humans have not provided conclusive or particularly promising answers with regard to: the prevention of general respiratory infections, the outcome of patients with respiratory infections, and to the possible better outcome of influenza vaccination. Consequently, at the current state of knowledge, there is no evidence that the correction of a vitamin D deficiency is useful to strengthen the immune system and to prevent or attenuate the course of infections in general and respiratory infections in particular.
However, this conclusion does not eliminate the fact that a widespread vitamin D deficiency exists and is particularly acute in the elderly population, especially if their mobility is reduced or null, as for guests of nursing homes. Plasma dosage of 25(OH) vitamin D is absolutely necessary in this population group in order to document the nutritional condition and to correct the deficiency according to current protocols. A relatively rapid correction requires the administration of high doses of vitamin D for a few weeks with precise remote control and always on prescription. A daily supplement may, however, be useful once the deficiency has been corrected to maintain the values achieved in view of the high frequency of recurrence and the modest contribution of vitamin D present only in some foods.
The correction of vitamin D deficiency has as its main objective the maintenance of bone health and good skeletal muscle function, which is also essential for the prevention of falls and the consequent complications that actually reduce life quality and expectancy of the patient. Whether the correction of vitamin D deficiency can also reduce the risk of metabolic and vascular diseases and support the immune system is still part of wishful thinking.