Vitamin D Prevents the Maladaptive Cycle of Local Inflammation and Secondary Injury that Leads to Poorer Outcomes

A recent large-scale epidemiological study suggested a possible link between vitamin D deficiency and the severity of COVID-19 cases among patients in the USA, France and the United Kingdom(84). This study correlated the low serum level of vitamin D with a higher C-reactive protein (CRP) level in COVID-19 patients based on previous findings(85, 86). In fact, multiple observational and intervention studies have suggested the beneficial effects of vitamin D on reducing circulating CRP and pro-inflammatory cytokines(86-90). This has a beneficial impact in lowering a heightened inflammation state that is associated with poorer outcomes(91-93). Vitamin D also modulates the renin-angiotensin cascade(94). A high expression of angiotensin converting enzyme (ACE) and angiotensin II, coupled with reduced expression of angiotensin converting enzyme 2 (ACE2) are common features in a pro-inflammatory state in acute respiratory distress syndrome (ARDS). Vitamin D reduces the susceptibility to acute lung injury (ALI) by inhibiting renin thereby angiotensin II biosynthesis(95-98). This may have a protective effect in preventing a “cytokine storm” that is often implicated in severe COVID-19 cases(84, 99).
Vitamin D also enhances the production of interleukin-10 (IL-10), a cytokine with potent anti-inflammatory properties(100). Increasing IL-10 favours the proliferation and differentiation of T helper cell 2 (Th2) and T regulator (T reg) cells over T helper cell 1 (Th1) and T helper cell 17 (Th 17) (101, 102). This could have an effect in promoting tolerance and controlling an exacerbated immune response(41). Furthermore, vitamin D supplementation reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages, by enhancing expression of MAPK phosphatase-1 and suppressing p38 activation(103-105). A persistent immune activation leads to an increased mortality in HIV patient. Vitamin D protects against the development of immune reconstitution inflammatory syndrome events in HIV patients, likely through downregulating CD38 expression on the surface of memory CD8+ T cells(106, 107). Vitamin D also decreases the expression of major histocompatibility complex (MHC) class II and their co-stimulatory molecules such as CD80, thereby decreasing T cell activation with persistent antigen presentation(108). It could be posited that these anti-inflammatory properties of vitamin D could have beneficial impacts on patients suffering from severe form of COVID-19.
In animal studies, it has been shown that vitamin D can reduce the severity of coronavirus illness such as the enteropathogenic porcine epidemic diarrhoea virus (PEDV)(109). Adding 155.5µg/kg diet 25(OH)D to the feed given to weaned pigs can have a protective effect on PEDV-induced inflammation and alleviate damage to the intestinal tracts(109). This is achieved by regulating autophagy, enhancing cathelicidins production and inhibiting jejuna mucosa interleukin-6 (IL-6) and interleukin-8 (IL-8) mRNA expression, hence lessening the severity of damage(109-111). The VDR-knockout mice model has demonstrated that vitamin D has protective effects on the integrity of epithelial cells lining the respiratory tract, by reducing lipopolysaccharides-induced acute lung injury(112). These animal studies suggest that active vitamin D could be effective in reducing the severity of acute lung injury and suppress a heightened inflammatory state in COVID-19 patients.