Potential benefit of vitamin D supplementation in people with respiratory illnesses, during the COVID-19 pandemic.

This review describes the evidence for the potential benefit of vitamin D supplementation in people with respiratory diseases who may have a higher susceptibility to coronavirus disease 2019 (COVID-19) infection and its consequences. Clinical evidence indicates that vitamin D may reduce the risk of both upper and lower respiratory tract infections and offers benefit particularly in people with vitamin D deficiency. Some evidence exists for a higher incidence of active tuberculosis (TB) in patients who are deficient in vitamin D. An association between low levels of 25(OH)D (the active form of vitamin D) and COVID-19 severity of illness and mortality has also been reported. In addition, low 25(OH)D levels are associated with poor outcomes in acute respiratory distress syndrome (ARDS). The cytokine storm experienced in severe COVID-19 infections results from excessive release of pro-inflammatory cytokines. Due to its immunomodulatory effects, adequate vitamin D levels may cause a decrease in the pro-inflammatory cytokines and an increase in the anti-inflammatory cytokines during COVID-19 infections. Vitamin D deficiency was found in 82.2% of hospitalized COVID-19 cases and 47.2% of population-based controls (p < 0.0001). The available evidence warrants an evaluation of vitamin D supplementation in susceptible populations with respiratory diseases, such as TB, and particularly in those who are deficient in vitamin D. This may mitigate against serious complications of COVID-19 infections or reduce the impact of ARDS in those who have been infected.

Immune variations throughout the course of tuberculosis treatment and its relationship with adrenal hormone changes in HIV-1 patients co-infected with Mycobacterium tuberculosis.

HIV infection is a major risk factor predisposing for Mycobacterium tuberculosis infection and progression to active tuberculosis (TB). As host immune response defines the course of infection, we aimed to identify immuno-endocrine changes over six-months of anti-TB chemotherapy in HIV+ people. Plasma levels of cortisol, DHEA and DHEA-S, percentages of CD4+ regulatory T cell subsets and number of IFN-γ-secreting cells were determined. Several cytokines, chemokines and C-reactive protein levels were measured. Results were correlated with clinical parameters as predictors of infection resolution and compared to similar data from HIV+ individuals, HIV-infected persons with latent TB infection and healthy donors. Throughout the course of anti-TB/HIV treatment, DHEA and DHEA-S plasma levels raised while cortisol diminished, which correlated to predictive factors of infection resolution. Furthermore, the balance between cortisol and DHEA, together with clinical assessment, may be considered as an indicator of clinical outcome after anti-TB treatment in HIV+ individuals. Clinical improvement was associated with reduced frequency of unconventional Tregs, increment in IFN-γ-secreting cells, diminution of systemic inflammation and changes of circulating cytokines and chemokines. This study suggests that the combined anti-HIV/TB therapies result in partial restoration of both, immune function and adrenal hormone plasma levels.

A double burden of tuberculosis and diabetes mellitus and the possible role of vitamin D deficiency.

Tuberculosis remains a major global health challenge, particularly in low-to-middle income countries such as China. At the same time, the country is facing a rapidly increasing diabetes incidence over the last 10 years. Diabetes aggravates the tuberculosis epidemic which poses a serious challenge in public health. In recent years, the high prevalence of vitamin D deficiency represents a global health problem, which is also associated with the risk of diabetes, and tuberculosis. Therefore, this review aims to provide an overall and updated understanding of the epidemiology of co-occurrence of tuberculosis and diabetes in China, and to elucidate the possible role of vitamin D deficiency. In conclusion, significant aggravation of the tuberculosis epidemic due to diabetes may exist in China for a relatively long period of time to come. Further, the double burden and its implications to public health in this country may be significantly influenced by the high prevalence of vitamin D deficiency. Bidirectional screening for tuberculosis and diabetes is recommended, and extra vitamin D may benefit especially in a situation of a heavy tuberculosis burden combined with prevalent vitamin D deficiency. Longitudinal studies to verify the role of vitamin D deficiency in the double burden, and trials on the effect of vitamin D supplementation are needed in the future.

The association between vitamin D deficiency and extrapulmonary tuberculosis: Case-control study.

Tuberculosis remains a public health issue worldwide. Identifying its risk factors, such as vitamin D deficiency, is mandatory so as to target the preventive strategies. We aimed to study the association between vitamin D deficiency and extrapulmonary tuberculosis. We conducted a case-control study including all cases of extrapulmonary tuberculosis hospitalized in the infectious diseases department over a two-year period from April 2017 until April 2019. We included 45 cases of extrapulmonary tuberculosis and 45 controls matched by gender and age. Vitamin D deficiency was significantly more frequent among cases (80% vs 37.7%; p < 0.001), with an odds ratio (OR) of 6.5 (IC95% = 2.5-16). The mean levels of vitamin D were significantly lower among cases (11.9 ± 8.8 vs 22.3 ± 11 ng/mL; p < 0.001). In the multivariate analysis, we found that vitamin D deficiency was an independent predictor of extrapulmonary tuberculosis (OR = 6.13; p < 0.001). The cutoff value of vitamin D predictor of extrapulmonary tuberculosis was 18.5 ng/mL which was associated with a sensitivity of 80% and a specificity of 62%. Our study provides strong evidence that vitamin D deficiency was an independent predictor of extrapulmonary tuberculosis. More studies are needed in order to evaluate the potential preventive role of vitamin D and the benefit of possible supplementation.

Micronutrient levels of tuberculosis patients during the intensive phase, a prospective cohort study.

INTRODUCTION: The objectives of this study were to estimate the micronutrient deficiency levels of tuberculosis patients at the start and end of the intensive phase, and to identify the predictors of micronutrient deficiencies in tuberculosis patients. METHODS: A prospective cohort study design was implemented. The sample size was calculated using Epi-info software. Systematic sampling technique was used. Descriptive statistics were used to estimate the micronutrient levels. The general linear model was used to predict the determinants of micronutrient level. RESULTS: At the start of DOTS (directly observed treatment strategy), 64% of tuberculosis patients had a serum iron level less than 60 µg/dl, 41.9% of tuberculosis patients had serum zinc level less than 52 µg/dl, 29.7% of tuberculosis patients had serum selenium level less than 70 ng/dl, 40.5% of tuberculosis patients had serum vitamin d level less than 20 ng/ml, and 60.4% of tuberculosis patients had urine iodine level of less than 60.4 µg/dl. At the end of the intensive phase, 16.7% of tuberculosis patients had a serum iron level less than 60 µg/dl, <1% of tuberculosis patients had serum zinc level less than 52 µg/dl, <1% of tuberculosis patients had serum selenium level less than 70 ng/dl, 20.4% of tuberculosis patients had serum vitamin d level less than 20 ng/ml, and 53% of tuberculosis patients had urine iodine level of less than 60.4 µg/dl. Serum iron level was affected by HIV infection, hookworm infection, and site of tuberculosis infection: serum vitamin d level was affected by HIV infection: and alcohol dependency affected the serum zinc level of tuberculosis patients during the course of tuberculosis treatments. CONCLUSION: Antituberculosis drugs were effective in normalizing the serum zinc and selenium level, but the serum level of iron, vitamin d and iodine were not normalized by the anti-tuberculosis drugs.

Ischemic stroke and disseminated tuberculosis in a child living with human immunodeficiency virus: a case report and review of the literature.

BACKGROUND: Cerebrovascular accidents are rare in children. Rates of stroke in children with human immunodeficiency virus infection are higher than in the uninfected population. CASE PRESENTATION: We report the case of a 19-month-old Ethiopian boy who presented with a left-sided body weakness of sudden onset. He was also diagnosed as having human immunodeficiency virus infection. Laboratory tests showed an iron deficiency anemia and imaging revealed tuberculosis of his lungs, spleen, and abdominal lymph nodes as well as an acute ischemic stroke of the right middle cerebral artery region. His symptoms improved after anti-tuberculosis drugs, antiretroviral treatment, and iron supplementation were initiated. CONCLUSIONS: Extrapulmonary tuberculosis should be considered a cause of sudden focal neurologic deficits in children with human immunodeficiency virus infection residing in endemic countries.

Serum selenium levels in tuberculosis patients: A systematic review and meta-analysis.

INTRODUCTION: Tuberculosis (TB) is associated with increased mortality. The high risk of micronutrients deficiency, including selenium, in TB patients is of great concern because it increases the risk of death. However, it is not clear whether selenium supplementation could improve the treatment outcomes in TB patients. We conducted a systematic review and meta-analysis to provide an update on the existing evidence about low selenium levels in TB patients. METHODS: In this systematic review and meta-analysis, EMBASE, Medline and the International Journal of Tuberculosis and Lung Disease were searched to identify observational studies on selenium and TB published up until April 2018. Studies comparing blood selenium levels in TB patients to controls were included. Data extraction was performed by two investigators. The quality of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Random effects analysis was performed to calculate the pooled effect size and 95% confidence interval (CI). RESULTS: Of the 605 studies initially identified, only six were eligible. Of them, four were carried out in Asia, and one each in Africa and South America. The random pooled effect size was 1.6 (CI: 0.9, 2.4). This means that the probability is 160% for an individual with TB to have low levels of selenium as compared to an individual without TB. Heterogeneity across the studies was substantial (I2 = 95.1%). Potential sources of heterogeneity included study design and selenium measurement methods. CONCLUSION: Our review provides compelling evidence that serum selenium is lower in TB patients as compared with controls. Therefore, it is advisable to individually assess selenium status in TB patients and decide whether selenium supplement is needed or not.

Role of essential trace elements in tuberculosis infection: A review article.

Malnutrition is one of the risk factors in tuberculosis (TB) infection. Mineral levels perturbation is seen in patients with TB. Moreover there are some strategies to starve pathogens of essential metals. Here we decided to conclude association between some essential elements and TB. Copper, calcium and iron are essential for hosts' immune system although calcium and iron are necessary for Mycobacterium tuberculosis vitality. Changing these elements alongside with anti-TB therapy is suggested for better treatment outcomes.

Low plasma vitamin A concentration is associated with tuberculosis in Moroccan population: a preliminary case control study.

BACKGROUND: Vitamin A plays numerous roles in immune system. Its deficiency alters both the innate and adaptive immunity. Previous results reported that the micronutrients deficiency, particularly vitamin A, is observed in patients with tuberculosis. Thus, we aimed in this study to assess vitamin A concentrations in Moroccan patients with tuberculosis to set up a large efficacy study of vitamin A supplementation for TB infected patients. Plasma retinol concentration was measured by HPLC in 44 recently diagnosed TB patients and 40 healthy controls. RESULTS: We showed that plasma vitamin A is significantly lower in tuberculosis patients as compared to healthy controls (p < 0.0001). Moreover, no significant association was found between vitamin A deficiency and, TB severity and patients' ages. CONCLUSION: Our study confirms the association between low vitamin A levels and tuberculosis disease.

Vitamin D deficiency and the risk of tuberculosis: a meta-analysis.

BACKGROUND AND AIM: To conduct meta-analyses of all published studies on various aspects of association between vitamin D and tuberculosis (TB). METHODS: PubMed and Web of Knowledge were searched for all properly controlled studies on vitamin D and TB. Pooled odds ratio, mean difference or standardized mean difference, and its corresponding 95% confidence interval were calculated with the Cochrane Review Manager 5.3. RESULTS: A significantly lower vitamin D level was found in TB patients vs controls; vitamin D deficiency (VDD) was associated with an increased risk of TB, although such an association was lacking in the African population and in the human immunodeficiency virus-infected African population. A significantly lower vitamin D level was found in human immunodeficiency virus-TB-coinfected African patients receiving antiretroviral treatment who developed TB-associated immune reconstitution inflammatory syndrome vs those who did not develop TB-associated immune reconstitution inflammatory syndrome. VDD was associated with an increased risk of developing active TB in those subjects with latent TB infection and with an increased risk of tuberculin skin test conversion/TB infection conversion, and the trend toward a lower vitamin D level in active TB patients vs latent TB infection subjects did not reach statistical significance, indicating that VDD was more likely a risk factor than a consequence of TB. This concept was further strengthened by our result that anti-TB treatment did not affect vitamin D level in TB patients receiving the treatment. CONCLUSION: Our analyses revealed an association between vitamin D and TB. VDD is more likely a risk factor for TB than its consequence. More studies are needed to determine whether vitamin D supplementation is beneficial to TB prevention and treatment.

Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis.

Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log10 CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log10 reduction in the spleen with animals treated with both SB-PT070 and RIF.

Vitamin D and airway infections: a European perspective.

Vitamin D has immuno-modulatory properties, and deficient levels of circulating 25-hydroxyvitamin D (<30 nmol/l) may contribute to increased risk of infectious illnesses. This narrative review summarises data on vitamin D status in Europe and updates results of randomised controlled trials (RCTs) regarding vitamin D and airway infections such as tuberculosis (TB) and acute upper respiratory tract infection. In Europe, the prevalence of vitamin D deficiency is up to 37% in the general population and up to 80% in nursing home residents and non-European immigrants. Half of TB patients have a migration background. While results of RCTs do not support the concept of beneficial adjunctive effects of vitamin D supplements in anti-TB treatment [odds ratio (OR) = 0.86; 95% CI 0.62-1.19], the few published RCTs on the prophylaxis of TB suggest some protective vitamin D effects in individuals with deficient circulating 25-hydroxyvitamin D levels. Regarding acute respiratory tract infection, RCTs indicate a significant risk reduction by vitamin D supplements [OR = 0.65; 95% confidence interval (CI) 0.50-0.85]. There is evidence that daily administration is more effective than high-dose bolus administration [OR = 0.48 (95% CI 0.30-0.77) vs. OR = 0.87 (95% CI 0.67-1.14)] and that individuals with deficient or insufficient (30-50 nmol/l) circulating 25-hydroxyvitamin D levels benefit most. Several vitamin D effects on innate immunity may explain these protective effects. In summary, there is possible evidence from RCTs for protective vitamin D effects on TB and likely evidence for protective effects on acute airway infection. Since vitamin D deficiency is prevalent in Europe, especially in institutionalised individuals and non-European immigrants, daily oral vitamin D intake, e.g. 1000 international units, is an inexpensive measure to ensure adequate vitamin D status in individuals at risk.

Vitamin D, serum 25(OH)D, LL-37 and polymorphisms in a Canadian First Nation population with endemic tuberculosis.

BACKGROUND: Canadian First Nation populations have experienced endemic and epidemic tuberculosis (TB) for decades. Vitamin D-mediated induction of the host defence peptide LL-37 is known to enhance control of pathogens such as Mycobacterium tuberculosis. OBJECTIVE: Evaluate associations between serum levels of 25-hydroxy vitamin D (25(OH)D) and LL-37, in adult Dene First Nation participants (N = 34) and assess correlations with single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP). DESIGN: Venous blood was collected from all participants at baseline (winter and summer) and in conjunction with taking vitamin D supplements (1,000 IU/day) (winter and summer). Samples were analysed using ELISA for concentrations of vitamin D and LL-37, and SNPs in the VDR and VDBP regions were genotyped. RESULTS: Circulating levels of 25(OH)D were not altered by vitamin D supplementation, but LL-37 levels were significantly decreased. VDBP and VDR SNPs did not correlate with serum concentrations of 25(OH)D, but LL-37 levels significantly decreased in individuals with VDBP D432E T/G and T/T, and with VDR SNP Bsm1 T/T genotypes. CONCLUSIONS: Our findings suggest that vitamin D supplementation may not be beneficial as an intervention to boost innate immune resistance to M. tuberculosis in the Dene population.

Impact of vitamin D supplementation on the outcome of tuberculosis treatment: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Vitamin D supplementation is believed to be beneficial in the treatment of patients with tuberculosis (TB), however, results from clinical trials have been inconclusive. METHODS: We performed a systematic literature search across MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Springer, EBSCO, ProQuest, HighWire Press, and Web of Science, published as of December 2013. We individually inspected citations and extracted data independently. We estimated pooled risk ratios (RR) and 95% confidence intervals (CI) using random-effect models. We also assessed risk of bias using the Jadad scale and the quality of the evidence using GRADE. We included all randomized controlled trials comparing vitamin D with or without standard TB therapy or placebo. RESULTS: A total of five studies were analyzed in our meta analysis covering 841 newly-diagnosed TB cases. Patients receiving vitamin D supplementation had a 39% reduced risk of sputum smear or culture positive after six weeks of anti-TB treatment than those in the control group, although this is not statistically significant (pooled RR 0.61, 95% CI 0.24 to 1.56, P = 0.30). Apart from an increased serum vitamin D level in the supplement group after eight weeks of treatment there was no evidence of any additional adverse effects related to vitamin D. CONCLUSIONS: The meta analysis results indicate that vitamin D supplementation does not seem to have any beneficial effect in the treatment of TB. Future rigorous randomized controlled trials are needed to explore whether the supplementation of vitamin D could shorten treatment duration and to confirm whether the polymorphisms of vitamin D receptor have any potentially beneficial effect.

Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients in India.

SETTING: Rifabutin (RBT) is reported to be as effective as and to have less inducing effect on cytochrome P450 enzymes than rifampicin against tuberculosis (TB). The optimal dose of RBT during ritonavir (RTV) co-administration remains a matter of debate. OBJECTIVE: To study the pharmacokinetics of 150 mg RBT thrice weekly during concomitant atazanavir/RTV administration in human immunodeficiency virus (HIV) infected TB patients. METHODS: This observational study was conducted in 16 adult HIV-infected TB patients being treated for TB with an RBT-containing regimen and an antiretroviral therapy regimen with RTV; the dose of RBT was 150 mg thrice weekly. Serial blood draws were performed at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 h after the drug was administered. Plasma RBT was estimated using high-performance liquid chromatography. RESULTS AND CONCLUSIONS: Peak RBT concentration was below the lower therapeutic limit (<0.3 µg/ml) in seven patients, while 10 patients had trough concentrations below the minimal inhibitory concentration against Mycobacterium tuberculosis (0.06 µg/ml), suggesting that the RBT dosage may be inadequate. Prospective studies in different settings are required to arrive at the proper therapeutic dose for RBT to be used during co-administration with RTV.

Carnitine deficiency and its possible risk factors in TB patients: first report.

AIM: To assess carnitine serum levels and possible risk factors of its deficiency in patients with TB. PATIENTS & METHODS: All newly diagnosed TB patients admitted to an infectious diseases ward were recruited. Demographic, clinical and paraclinical characteristics of the patients were collected. Total carnitine serum concentrations were measured. To investigate factors that can predict carnitine deficiency, logistic regression analysis with odds ratio and 95% CI was performed. RESULTS: The mean ± standard deviation of carnitine serum levels of patients was 43.77 ± 32.92 µmol/l. Carnitine deficiency was detected in 47.7% of the study population. According to the final model of multivariate logistic regression analysis, increased serum triglyceride levels and hypoalbuminemia were identified as predictive factors of carnitine deficiency in TB patients aged over 35 years old. CONCLUSION: Nearly half of Iranian patients with TB were carnitine-deficient. Increased serum triglyceride levels and hypoalbuminemia were identified as independent risk factors of carnitine deficiency in patients aged over 35 years. Considering malnutrition as a major risk factor of TB and the safety of carnitine supplementation, use of carnitine as an adjunctive modality instead of other standard interventions may show beneficial effects in patients with TB.

Low plasma levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: implications in host-based chemotherapy.

OBJECTIVE: The aim of this study was to estimate the concentration of cholecalciferol and 13-cis-retinoic acid (RA) in the plasma and pleural fluid of patients with tuberculosis (TB) against controls. METHODS: Plasma levels of cholecalciferol and 13-cis-RA were measured in 22 patients with TB and healthy controls and their pleural fluids levels were measured in 6 TB patients and diseased controls by established high-performance liquid chromatography-based procedure. RESULTS: Cholecalciferol levels in plasma and pleural fluid of patients with TB and healthy controls were 67.45 (10.71) nmol/L and 21.40 (8.58) nmol/L compared with 117.43 (18.40) nmol/L (P < 0.001) and 94.73 (33.34) nmol/L (P = 0.0049), respectively. 13-cis-RA level in the plasma of patients with TB and healthy controls were 1.51 (0.72) nmol/L and 6.67 (0.81) nmol/L (P < 0.001), respectively. 13-cis-RA was not detectable in pleural fluid. The levels of both the agents were lower in patients with TB than in controls. CONCLUSION: It was observed that in patients with TB there is a combined deficiency of cholecalciferol and 13-cis-RA compared with healthy volunteers. Because cholecalciferol and 13-cis-RA are in equilibrium with active ingredients of vitamins A and D, we feel that there is a combined deficiency of these vitamins in patients with TB. There is an evidence that concomitant vitamin A and D supplementation can kill intracellular Mycobacterium tuberculosis in vitro. Therefore, the observations made in this study can pave the path for a trial of combined supplementation of available formulations of vitamin A and D (cholecalciferol and 13-cis-RA) for novel anti-tubercular drug therapy. Because such an approach is host-based it has potential to treat even multidrug-resistant and extensively drug-resistant forms of TB.

Interferon γ assays in the diagnosis of tuberculosis infection in psoriasis patients who are candidates for biologic therapies.

Although there is no doubt that biologic agents are an effective alternative for the treatment of moderate and severe psoriasis, anti-tumor necrosis factor α therapy has been associated with reactivation of latent tuberculosis infection. Tuberculin skin testing (TST) is used to diagnose tuberculosis infection but it has low specificity in patients who have received the Mycobacterium bovis BCG vaccine and low sensitivity in patients with altered cell-mediated immunity. In vitro assays based on the detection of interferon γ released by T cells stimulated by specific Mycobacterium tuberculosis antigens have emerged as an option for the diagnosis of tuberculosis infection. The results to date show that they are a viable alternative to TST thanks to their higher specificity and sensitivity. Furthermore, these assays are also proving to have high negative predictive value, meaning that we might be able to use them without TST in the short to medium term.

Oral immunogenicity of potato-derived antigens to Mycobacterium tuberculosis in mice.

The novel use of transgenic plants as vectors for the expression of viral and bacterial antigens has been increasingly tested as an alternative methodology for the production and delivery of experimental oral vaccines. Here, we examined the immunogenicity of combined plant-made vaccines that include four genes encoding immune-dominant antigens from Mycobacterium tuberculosis. Compared with the wild type and other control groups, mice treated with the combined plant-made vaccines showed significantly higher levels of interferon-γ and interleukin-2 production in response to all four proteins, and higher levels of antigen-specific CD4(+) and CD8(+) T-cell responses and immunoglobulin (Ig) G and IgA titers. These results suggest that combined plant-made vaccines can induce immunogenicity against M. tuberculosis through the induction of stronger Th1-associated immune responses. This is the first report of an orally delivered combined plant-made vaccine against tuberculosis priming an antigen-specific Th1 response, a comprehensive effect including both mucosal and systemic immune responses.