## 5 Potential Roles for Vitamin D as a Therapeutic Option in Inflammasome Disorders
### Infection  
VD supplementation in respiratory tract infections has received significant attention and many trials have been conducted to evaluate the role of VD in respiratory infections. VDD has been identified as an independent risk factor for active pulmonary tuberculosis infection, with the strongest association at levels below 25 nmol/L (<10 ng/mL) [78; 79]. One very large trial of weekly bolus oral dosing of VD\({}_{3}\) in 8851 VDD Mongolian children found no benefit to supplementation over 3 years as a preventative for developing pulmonary tuberculosis, although the event rate was very low (46/8851; 0.52%) [80]. Nine small- to medium-sized RCTs, including a total of 1868 patients, have examined the utility of 25(OH)-VD\({}_{3}\) supplementation as an add-on therapy in patients who already have active pulmonary tuberculosis [81; 82; 83]. There was significant heterogeneity between dosing regimens among the trials (daily dosing, weekly/monthly bolus dosing, oral/intramuscular administration), while a number of trials did not test baseline or posttherapy 25(OH)-VD levels, making comparison and meta-analysis difficult. Four trials demonstrated improved sputum culture conversion [82; 83; 84; 85], while three trials did not [81; 86; 87]. One trial found no difference in mortality, although posttherapy 25(OH)-VD levels remained low [88], while four measured tuberculosis scores, with only one of these showing positive results [83; 85; 87; 89]. There is also evidence of a role for VDD in predisposition to influenza infections. Early evidence came from observations of the seasonal nature of influenza infections [90], and several large cohort studies [91; 92] and one meta-analysis [93] have since found an inverse association between VD status and risk of respiratory tract infections. Trials with moderate heterogeneity and significantly varied dosing/administration protocols show possible benefit, the strongest with daily/weekly rather than bolus intermittent monthly dosing. Given that VD has a wide range of modulating actions on immune activity, it is unclear whether an inflammasome-attenuating response is mediating the apparent effect in these conditions. In tuberculosis, an intact IL-1\(\beta\) signalling response is important for host defence in murine models, but this is independent of NLRPP3 inflammasome activation [94], and it is possible that mycobacterial-induced inflammasome activation may promote persistent infection [95]. In respiratory tract infections such as influenza, the innate immune system inflammatory response is crucial to being able to mediate viral clearance and repair [96]. However, dysregulated or excessive inflammasome-mediated responses are associated with poor outcomes [96]. In patients with avian influenza, analysis of bronchoalveolar lavage and plasma samples found increased levels of IL-1\(\beta\) and IL-18 were poor prognostic markers [97; 98]. It is possible to speculate that VD-mediated inhibition of inflammasome activation might be helpful in the most severe form of infection--sepsis. In sepsis, maladaptive inflammatory responses that would normally be protective become harmful and lead to organ dysfunction [99]. A hallmark of the septic response is high levels of the inflammasome-dependent IL-1\(\beta\)[99]. A medium-sized trial of a mixed intensive care unit (ICU) cohort that included septic patients randomised 475 VDD patients to receive either high-dose pulse VD\({}_{3}\) monthly or a placebo. While the main outcomes were not different in the general population, pre-determined subgroup analysis of patients with 25(OH)-VD levels \(<\)30 nmol/L (\(<\)12 ng/mL) showed significant benefits in mortality at 28 days and lasting until up to 6 months [100]. In this context, there has recently been intense interest in VD supplementation in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, known as COVID-19 [101; 102; 103].