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Vitamin D for the Immune System in Cystic Fibrosis (DISC): a double-blind, multicenter, randomized, placebo-controlled clinical trial.
Tangpricha, V, Lukemire, J, Chen, Y, Binongo, JNG, Judd, SE, Michalski, ES, Lee, MJ, Walker, S, Ziegler, TR, Tirouvanziam, R, et al
The American journal of clinical nutrition. 2019;109(3):544-553
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Patients with cystic fibrosis (CF) have a mutation in a particular gene which results in derangements in chloride transport across epithelial surfaces, leading to abnormally thickened mucus on the surfaces of the lung, pancreas, intestines, and other organs. The aim of this study was to investigate the impact of high-dose vitamin D3 administered to adults with CF during and after an acute pulmonary exacerbation. The study is a double-blind, randomised, placebo-controlled clinical trial. Subjects were randomly assigned and stratified to one of the two groups: vitamin D (5 capsules of vitamin D3 containing 50,000 IU) or placebo (5 capsules that were identical in size, shape, and colour to the vitamin D3 capsule). Results demonstrated that high-dose vitamin D3 administration to adults with CF initiated at the time of a pulmonary exacerbation did not improve time to next pulmonary exacerbation or 1 year survival. Authors conclude that a high-dose vitamin D3 bolus, combined with maintenance therapy given to adults with CF during acute pulmonary exacerbation of CF did not improve 1 year survival or recovery of lung function.
Abstract
BACKGROUND Patients with cystic fibrosis (CF) have increased risk of vitamin D deficiency owing to fat malabsorption and other factors. Vitamin D deficiency has been associated with increased risk of pulmonary exacerbations of CF. OBJECTIVES The primary objective of this study was to examine the impact of a single high-dose bolus of vitamin D3 followed by maintenance treatment given to adults with CF during an acute pulmonary exacerbation on future recurrence of pulmonary exacerbations. METHODS This was a multicenter, double-blind, placebo-controlled, intent-to-treat clinical trial. Subjects with CF were randomly assigned to oral vitamin D3 given as a single dose of 250,000 International Units (IU) or to placebo within 72 h of hospital admission for an acute pulmonary exacerbation, followed by 50,000 IU of vitamin D3 or an identically matched placebo pill taken orally every other week starting at 3 mo after random assignment. The primary outcome was the composite endpoint of the time to next pulmonary exacerbation or death within 1 y. The secondary outcomes included circulating concentrations of the antimicrobial peptide cathelicidin and recovery of lung function as assessed by the percentage of predicted forced expiratory volume in 1 s (FEV1%). RESULTS A total of 91 subjects were enrolled in the study. There were no differences between the vitamin D3 and placebo groups in time to next pulmonary exacerbation or death at 1 y. In addition, there were no differences in serial recovery of lung function after pulmonary exacerbation by FEV1% or in serial concentrations of plasma cathelicidin. CONCLUSIONS Vitamin D3 initially given at the time of pulmonary exacerbation of CF did not alter the time to the next pulmonary exacerbation, 12-mo mortality, serial lung function, or serial plasma cathelicidin concentrations. This trial was registered at clinicaltrials.gov as NCT01426256.
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The Vitamin D for Enhancing the Immune System in Cystic Fibrosis (DISC) trial: Rationale and design of a multi-center, double-blind, placebo-controlled trial of high dose bolus administration of vitamin D3 during acute pulmonary exacerbation of cystic fibrosis.
Tangpricha, V, Smith, EM, Binongo, J, Judd, SE, Ziegler, TR, Walker, S, Tirouvanziam, R, Zughaier, SM, Lee, MJ, Chesdachai, S, et al
Contemporary clinical trials communications. 2017;:39-45
Abstract
Vitamin D deficiency is highly prevalent in children and adults with cystic fibrosis (CF). Recent studies have found an association between vitamin D status and risk of pulmonary exacerbations in children and adults with CF. The ongoing Vitamin D for enhancing the Immune System in Cystic fibrosis (DISC) study is a multi-center, double-blind, randomized, placebo-controlled trial that will test the hypothesis of whether high dose vitamin D given as a single oral bolus of 250,000 IU to adults with CF during a pulmonary exacerbation followed by a maintenance dose of vitamin D will improve time to next pulmonary exacerbation and re-hospitalization, improve survival and lung function compared to placebo and reduce the rates of pulmonary exacerbation,. Subjects will be randomized 1:1 at each clinical site to vitamin D or placebo within 72 hours of hospital admission for pulmonary exacerbation. Clinical follow-up visits will occur at 1, 2, 3, and 7 days, and 1, 3, 6 and 12 months after randomization. Blood and sputum will be collected and determination of clinical outcomes will be assessed at each visit. The primary endpoint will be the time to next pulmonary exacerbation requiring antibiotics, re-hospitalization or death. The secondary endpoints will include lung function assessed by forced expiratory volume in 1 second (FEV1), blood markers of inflammatory cytokines, anti-microbial peptide expression by peripheral blood mononuclear cells and circulating concentrations in blood. Other exploratory endpoints will examine the phenotype of neutrophils and monocyte/macrophages in sputum. Nutritional status will be assessed by 3 day food records and food frequency questionnaire.
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Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D3 administration.
Alvarez, JA, Chong, EY, Walker, DI, Chandler, JD, Michalski, ES, Grossmann, RE, Uppal, K, Li, S, Frediani, JK, Tirouvanziam, R, et al
Metabolism: clinical and experimental. 2017;:31-41
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Abstract
BACKGROUND Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown. OBJECTIVE We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation. DESIGN Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation. RESULTS Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways-predominantly representing amino acid pathways-differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment. CONCLUSIONS Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting.
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Neutrophil plasticity enables the development of pathological microenvironments: implications for cystic fibrosis airway disease.
Margaroli, C, Tirouvanziam, R
Molecular and cellular pediatrics. 2016;(1):38
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Abstract
INTRODUCTION The pathological course of several chronic inflammatory diseases, including cystic fibrosis, chronic obstructive pulmonary disease, and rheumatoid arthritis, features an aberrant innate immune response dominated by neutrophils. In cystic fibrosis, neutrophil burden and activity of neutrophil elastase in the extracellular fluid have been identified as strong predictors of lung disease severity. REVIEW Although neutrophils are generally considered to be rigid, pre-programmed effector leukocytes, recent studies suggest extensive plasticity in how neutrophil functions unfold upon recruitment to peripheral tissues, and how they choose their ultimate fate. Indeed, upon migration to cystic fibrosis airways, neutrophils display dysregulated lifespan, metabolic activation, and altered effector and regulatory functions, consistent with profound adaptation and phenotypic reprogramming. Licensed by signals present in cystic fibrosis airway microenvironment to survive and develop these novel functions, neutrophils orchestrate, in partnership with the epithelium and with the resident microbiota, the evolution of a pathological microenvironment. This microenvironment is defined by altered proteolytic, redox, and metabolic balance and the presence of stable luminal structures in which neutrophils and microbes coexist. CONCLUSIONS The elucidation of molecular mechanisms driving neutrophil plasticity in vivo will open new treatment opportunities designed to modulate, rather than block, the crucial adaptive functions fulfilled by neutrophils. This review aims to outline emerging mechanisms of neutrophil plasticity and their participation in the building of pathological microenvironments in the context of cystic fibrosis and other diseases with similar features.
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High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial.
Johnson, K, McEvoy, CE, Naqvi, S, Wendt, C, Reilkoff, RA, Kunisaki, KM, Wetherbee, EE, Nelson, D, Tirouvanziam, R, Niewoehner, DE
International journal of chronic obstructive pulmonary disease. 2016;:799-807
Abstract
BACKGROUND Clinical outcomes are worse in patients with COPD and chronic bronchitis. N-acetylcysteine (NAC) is commonly prescribed for such patients but with uncertain clinical benefits. We postulated that oral NAC, at much larger doses than those ordinarily prescribed, would improve clinical outcomes in a subset of patients with COPD and chronic bronchitis. OBJECTIVE The aim of this study was to determine whether very high-dose NAC would improve respiratory health status in patients with COPD and chronic bronchitis. METHODS Patients with COPD and chronic bronchitis were enrolled in a randomized, controlled, double-blinded trial. Patients received oral NAC (1,800 mg) or matching placebo twice daily for 8 weeks in addition to their usual respiratory medications. The primary outcome, respiratory health status, was assessed by changes in the St George's Respiratory Questionnaire. The effects of NAC on lung function and circulating markers of oxidative stress and inflammation were also evaluated. RESULTS We terminated the study prematurely because new external information suggested the possibility of a safety issue. Of the planned 130 patients, 51 were randomized and 45 (22 in the placebo arm and 23 in the NAC arm) completed the study. There was no statistically significant difference between changes in the St George's Respiratory Questionnaire total score, comparing NAC to placebo (adjusted mean difference, 0.1 U; 95% CI, -7.8 to 8.18 U; P=0.97). There were also no significant NAC-related improvements in any of the secondary outcomes. CONCLUSION In this 8-week trial, we were unable to show any clinical benefit from a very high dose of NAC in patients with COPD and chronic bronchitis.
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Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.
Conrad, C, Lymp, J, Thompson, V, Dunn, C, Davies, Z, Chatfield, B, Nichols, D, Clancy, J, Vender, R, Egan, ME, et al
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2015;(2):219-27
Abstract
PURPOSE To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways. METHODS A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. ENDPOINTS primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF. RESULTS Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14). CONCLUSIONS NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.
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High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis.
Tirouvanziam, R, Conrad, CK, Bottiglieri, T, Herzenberg, LA, Moss, RB, Herzenberg, LA
Proceedings of the National Academy of Sciences of the United States of America. 2006;(12):4628-33
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Abstract
Neutrophilic airway inflammation is a hallmark of cystic fibrosis (CF). As high oxidant producers, airway neutrophils contribute largely to the systemic redox imbalance seen in CF. In turn, this chronic and profound imbalance can impact circulating neutrophils before their migration into airways. Indeed, in 18 CF patients with stable disease, blood neutrophils were readily deficient in the pivotal antioxidant glutathione (P = 0.003, compared with 9 healthy controls). In a phase 1 study, this deficiency was improved (P = 0.025) by the glutathione prodrug N-acetylcysteine, given orally in high doses (0.6 to 1.0 g three times daily, for 4 weeks). This treatment was safe and markedly decreased sputum elastase activity (P = 0.006), the strongest predictor of CF pulmonary function. Consistently, neutrophil burden in CF airways was decreased upon treatment (P = 0.003), as was the number of airway neutrophils actively releasing elastase-rich granules (P = 0.005), as measured by flow cytometry. Pulmonary function measures were not improved, as expected with short-term treatment. After excluding data from subjects without baseline airway inflammation, positive treatment effects were more pronounced and included decreased sputum IL-8 levels (P = 0.032). Thus, high-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF.